Pharmaceutics

13 pages, 3318 KiB

Open AccessEditor’s ChoiceArticle

Flexible Coatings Facilitate pH-Targeted Drug Release via Self-Unfolding Foils: Applications for Oral Drug Delivery

by Carmen Milián-Guimerá, Laura De Vittorio, Reece McCabe, Nuray Göncü, Samvrta Krishnan, Lasse Højlund Eklund Thamdrup, Anja Boisen and Mahdi Ghavami

Pharmaceutics 2024, 16(1), 81; https://doi.org/10.3390/pharmaceutics16010081 - 6 Jan 2024

Cited by 1 | Viewed by 1887

Abstract

Ingestible self-configurable proximity-enabling devices have been developed as a non-invasive platform to improve the bioavailability of drug compounds via swellable or self-unfolding devices. Self-unfolding foils support unidirectional drug release in close proximity to the intestinal epithelium, the main drug absorption site following oral [...] Read more.

Ingestible self-configurable proximity-enabling devices have been developed as a non-invasive platform to improve the bioavailability of drug compounds via swellable or self-unfolding devices. Self-unfolding foils support unidirectional drug release in close proximity to the intestinal epithelium, the main drug absorption site following oral administration. The foils are loaded with a solid-state formulation containing the active pharmaceutical ingredient and then coated and rolled into enteric capsules. The coated lid must remain intact to ensure drug protection in the rolled state until targeted release in the small intestine after capsule disintegration. Despite promising results in previous studies, the deposition of an enteric top coating that remains intact after rolling is still challenging. In this study, we compare different mixtures of enteric polymers and a plasticizer, PEG 6000, as potential coating materials. We evaluate mechanical properties as well as drug protection and targeted release in gastric and intestinal media, respectively. Commercially available Eudragit^® FL30D-55 appears to be the most suitable material due to its high strain at failure and integrity after capsule fitting. In vitro studies of coated foils in gastric and intestinal media confirm successful pH-triggered drug release. This indicates the potential advantage of the selected material in the development of self-unfolding foils for oral drug delivery. Full article

(This article belongs to the Special Issue Nano and Microdevices for Targeted Drug Delivery)

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25 pages, 4065 KiB

Open AccessEditor’s ChoiceArticle

Material-Sparing Feasibility Screening for Hot Melt Extrusion

by Amanda Pluntze, Scott Beecher, Maria Anderson, Dillon Wright and Deanna Mudie

Pharmaceutics 2024, 16(1), 76; https://doi.org/10.3390/pharmaceutics16010076 - 5 Jan 2024

Viewed by 1688

Abstract

Hot melt extrusion (HME) offers a high-throughput process to manufacture amorphous solid dispersions. A variety of experimental and model-based approaches exist to predict API solubility in polymer melts, but these methods are typically aimed at determining the thermodynamic solubility and do not take [...] Read more.

Hot melt extrusion (HME) offers a high-throughput process to manufacture amorphous solid dispersions. A variety of experimental and model-based approaches exist to predict API solubility in polymer melts, but these methods are typically aimed at determining the thermodynamic solubility and do not take into account kinetics of dissolution or the associated degradation of the API during thermal processing, both of which are critical considerations in generating a successful amorphous solid dispersion by HME. This work aims to develop a material-sparing approach for screening manufacturability of a given pharmaceutical API by HME using physically relevant time, temperature, and shear. Piroxicam, ritonavir, and phenytoin were used as model APIs with PVP VA64 as the dispersion polymer. We present a screening flowchart, aided by a simple custom device, that allows rapid formulation screening to predict both achievable API loadings and expected degradation from an HME process. This method has good correlation to processing with a micro compounder, a common HME screening industry standard, but only requires 200 mg of API or less. Full article

(This article belongs to the Special Issue Research on Hot Melt Extrusion Processing for Drug Formulation and Drug Delivery)

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18 pages, 3677 KiB

Open AccessEditor’s ChoiceArticle

New Formulation–Microporation Combination Approaches to Delivering Ciclopirox across Human Nails

by Juliana Kishishita, Camila de Almeida Perez Pimenta, Danielle Patricia Cerqueira Macedo, M. Begoña Delgado-Charro and Leila Bastos Leal

Pharmaceutics 2024, 16(1), 72; https://doi.org/10.3390/pharmaceutics16010072 - 4 Jan 2024

Viewed by 1106

Abstract

Topical treatments for onychomycosis are of interest to those seeking to avoid systemic drug interactions and to improve systemic safety. This work aimed to develop aqueous-based, simple, and cost-effective vehicles that provide high solubility for ciclopirox and enable the delivery of an active [...] Read more.

Topical treatments for onychomycosis are of interest to those seeking to avoid systemic drug interactions and to improve systemic safety. This work aimed to develop aqueous-based, simple, and cost-effective vehicles that provide high solubility for ciclopirox and enable the delivery of an active through channels created by nail microporation. Following solubility tests, aqueous gels and thermogels based on hydroxypropylmethylcellulose and poloxamer 407, respectively, were loaded with 8% and 16% ciclopirox. Their performance was then compared to the marketed lacquer Micolamina^® in in vitro release tests with artificial membranes and in in vitro permeation tests with human nail clippings with and without poration. Finally, a microbiological assay compared the best gel formulations and the reference product. Little correlation was observed between the in vitro release and the permeation data, and the drug release was highly membrane-dependent. Ciclopirox nail retention in single-dose, porated nails tests was larger than in daily-dosing, non-porated nail conditions. The series of new gel and thermogel vehicles delivered ciclopirox more effectively than Micolamina^® in single-dose, porated nail experiments. The inhibition of Trichophyton rubrum activity was significantly increased with microporated nails when the gel formulations were applied but not with Micolamina^®. Overall, the results suggest that the new vehicles could be successfully combined with nail microporation to improve the drug delivery and efficacy of topical antifungal medication while reducing the dosing frequency, facilitating patients’ adherence. Full article

(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery, 2nd Edition)

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18 pages, 3524 KiB

Open AccessEditor’s ChoiceReview

Innovative Phosphorene Nanoplatform for Light Antimicrobial Therapy

by Elisa Passaglia and Antonella Sgarbossa

Pharmaceutics 2023, 15(12), 2748; https://doi.org/10.3390/pharmaceutics15122748 - 9 Dec 2023

Viewed by 2195

Abstract

Over the past few years, antibiotic resistance has reached global dimensions as a major threat to public health. Consequently, there is a pressing need to find effective alternative therapies and therapeutic agents to combat drug-resistant pathogens. Photodynamic therapy (PDT), largely employed as a [...] Read more.

Over the past few years, antibiotic resistance has reached global dimensions as a major threat to public health. Consequently, there is a pressing need to find effective alternative therapies and therapeutic agents to combat drug-resistant pathogens. Photodynamic therapy (PDT), largely employed as a clinical treatment for several malignant pathologies, has also gained importance as a promising antimicrobial approach. Antimicrobial PDT (aPDT) relies on the application of a photosensitizer able to produce singlet oxygen (¹O₂) or other cytotoxic reactive oxygen species (ROS) upon exposure to appropriate light, which leads to cell death after the induced photodamage. Among different types of 2D nanomaterials with antimicrobial properties, phosphorene, the exfoliated form of black phosphorus (bP), has the unique property intrinsic photoactivity exploitable for photothermal therapy (PTT) as well as for PDT against pathogenic bacteria. Full article

(This article belongs to the Special Issue Photodynamic Therapy: Rising Star in Pharmaceutical Applications)

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22 pages, 4190 KiB

Open AccessEditor’s ChoiceArticle

Investigation on Electrospun and Solvent-Casted PCL-PLGA Blends Scaffolds Embedded with Induced Pluripotent Stem Cells for Tissue Engineering

by Mariella Rosalia, Martina Giacomini, Erika Maria Tottoli, Rossella Dorati, Giovanna Bruni, Ida Genta, Enrica Chiesa, Silvia Pisani, Maurilio Sampaolesi and Bice Conti

Pharmaceutics 2023, 15(12), 2736; https://doi.org/10.3390/pharmaceutics15122736 - 6 Dec 2023

Viewed by 1294

Abstract

The design, production, and characterisation of tissue-engineered scaffolds made of polylactic-co-glycolic acid (PLGA), polycaprolactone (PCL) and their blends obtained through electrospinning (ES) or solvent casting/particulate leaching (SC) manufacturing techniques are presented here. The polymer blend composition was chosen to always obtain a prevalence [...] Read more.

The design, production, and characterisation of tissue-engineered scaffolds made of polylactic-co-glycolic acid (PLGA), polycaprolactone (PCL) and their blends obtained through electrospinning (ES) or solvent casting/particulate leaching (SC) manufacturing techniques are presented here. The polymer blend composition was chosen to always obtain a prevalence of one of the two polymers, in order to investigate the contribution of the less concentrated polymer on the scaffolds’ properties. Physical–chemical characterization of ES scaffolds demonstrated that tailoring of fibre diameter and Young modulus (YM) was possible by controlling PCL concentration in PLGA-based blends, increasing the fibre diameter from 0.6 to 1.0 µm and reducing the YM from about 22 to 9 MPa. SC scaffolds showed a “bubble-like” topography, caused by the porogen spherical particles, which is responsible for decreasing the contact angles from about 110° in ES scaffolds to about 74° in SC specimens. Nevertheless, due to phase separation within the blend, solvent-casted samples displayed less reproducible properties. Furthermore, ES samples were characterised by 10-fold higher water uptake than SC scaffolds. The scaffolds suitability as iPSCs culturing support was evaluated using XTT assay, and pluripotency and integrin gene expression were investigated using RT-PCR and RT-qPCR. Thanks to their higher wettability and appropriate YM, SC scaffolds seemed to be superior in ensuring high cell viability over 5 days, whereas the ability to maintain iPSCs pluripotency status was found to be similar for ES and SC scaffolds. Full article

(This article belongs to the Special Issue Electrospun Fibers: Advancement in Drug Delivery, Controlled Release, and Tissue Regeneration)

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22 pages, 2695 KiB

Open AccessEditor’s ChoiceReview

Advances in NIR-Responsive Natural Macromolecular Hydrogel Assembly Drugs for Cancer Treatment

by Chenyu Zhao, Boyue Pan, Tianlin Wang, Huazhe Yang, David Vance, Xiaojia Li, Haiyang Zhao, Xinru Hu, Tianchang Yang, Zihao Chen, Liang Hao, Ting Liu and Yang Wang

Pharmaceutics 2023, 15(12), 2729; https://doi.org/10.3390/pharmaceutics15122729 - 4 Dec 2023

Cited by 2 | Viewed by 1640

Abstract

Cancer is a serious disease with an abnormal proliferation of organ tissues; it is characterized by malignant infiltration and growth that affects human life. Traditional cancer therapies such as resection, radiotherapy and chemotherapy have a low cure rate and often cause irreversible damage [...] Read more.

Cancer is a serious disease with an abnormal proliferation of organ tissues; it is characterized by malignant infiltration and growth that affects human life. Traditional cancer therapies such as resection, radiotherapy and chemotherapy have a low cure rate and often cause irreversible damage to the body. In recent years, since the traditional treatment of cancer is still very far from perfect, researchers have begun to focus on non-invasive near-infrared (NIR)-responsive natural macromolecular hydrogel assembly drugs (NIR-NMHADs). Due to their unique biocompatibility and extremely high drug encapsulation, coupling with the spatiotemporal controllability of NIR, synergistic photothermal therapy (PTT), photothermal therapy (PDT), chemotherapy (CT) and immunotherapy (IT) has created excellent effects and good prospects for cancer treatment. In addition, some emerging bioengineering technologies can also improve the effectiveness of drug delivery systems. This review will discuss the properties of NIR light, the NIR-functional hydrogels commonly used in current research, the cancer therapy corresponding to the materials encapsulated in them and the bioengineering technology that can assist drug delivery systems. The review provides a constructive reference for the optimization of NIR-NMHAD experimental ideas and its application to human body. Full article

(This article belongs to the Collection Advanced Pharmaceutical Science and Technology)

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58 pages, 12931 KiB

Open AccessEditor’s ChoiceReview

Podophyllotoxin: Recent Advances in the Development of Hybridization Strategies to Enhance Its Antitumoral Profile

by Carolina Miranda-Vera, Ángela Patricia Hernández, Pilar García-García, David Díez, Pablo Anselmo García and María Ángeles Castro

Pharmaceutics 2023, 15(12), 2728; https://doi.org/10.3390/pharmaceutics15122728 - 4 Dec 2023

Cited by 4 | Viewed by 1647

Abstract

Podophyllotoxin is a naturally occurring cyclolignan isolated from rhizomes of Podophyllum sp. In the clinic, it is used mainly as an antiviral; however, its antitumor activity is even more interesting. While podophyllotoxin possesses severe side effects that limit its development as an anticancer [...] Read more.

Podophyllotoxin is a naturally occurring cyclolignan isolated from rhizomes of Podophyllum sp. In the clinic, it is used mainly as an antiviral; however, its antitumor activity is even more interesting. While podophyllotoxin possesses severe side effects that limit its development as an anticancer agent, nevertheless, it has become a good lead compound for the synthesis of derivatives with fewer side effects and better selectivity. Several examples, such as etoposide, highlight the potential of this natural product for chemomodulation in the search for new antitumor agents. This review focuses on the recent chemical modifications (2017–mid-2023) of the podophyllotoxin skeleton performed mainly at the C-ring (but also at the lactone D-ring and at the trimethoxyphenyl E-ring) together with their biological properties. Special emphasis is placed on hybrids or conjugates with other natural products (either primary or secondary metabolites) and other molecules (heterocycles, benzoheterocycles, synthetic drugs, and other moieties) that contribute to improved podophyllotoxin bioactivity. In fact, hybridization has been a good strategy to design podophyllotoxin derivatives with enhanced bioactivity. The way in which the two components are joined (directly or through spacers) was also considered for the organization of this review. This comprehensive perspective is presented with the aim of guiding the medicinal chemistry community in the design of new podophyllotoxin-based drugs with improved anticancer properties. Full article

(This article belongs to the Special Issue Recent Advances in Drug Targeting for Cancer Treatment)

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10 pages, 746 KiB

Open AccessEditor’s ChoiceArticle

Photodynamic Therapy Supported by Antitumor Lipids

by Mladen Korbelik

Pharmaceutics 2023, 15(12), 2723; https://doi.org/10.3390/pharmaceutics15122723 - 3 Dec 2023

Viewed by 1074

Abstract

Photodynamic therapy (PDT) destroys tumors by generating cytotoxic oxidants that induce oxidative stress in targeted cancer cells. Antitumor lipids developed for cancer therapy act also by inflicting similar stress. The present study investigated whether tumor response to PDT can be improved by adjuvant [...] Read more.

Photodynamic therapy (PDT) destroys tumors by generating cytotoxic oxidants that induce oxidative stress in targeted cancer cells. Antitumor lipids developed for cancer therapy act also by inflicting similar stress. The present study investigated whether tumor response to PDT can be improved by adjuvant treatment with such lipids using the prototype molecule edelfosine. Cellular stress intensity following Photofrin-based PDT, edelfosine treatment, or their combination was assessed by the expression of heat shock protein 70 (HSP70) on the surface of treated SCCVII tumor cells by FITC-conjugated anti-HSP70 antibody staining and flow cytometry. Surface HSP70 levels that became elevated after either PDT or edelfosine rose much higher after their combined treatment. The impact of Photofrin-PDT-plus-edelfosine treatment was studied with three types of tumor models grown in syngeneic mice. With both SCCVII squamous cell carcinomas and MCA205 fibrosarcoma, the greatest impact was with edelfosine peritumoral injection at 24 h after PDT, which substantially improved tumor cure rates. With Lewis lung carcinomas, edelfosine was highly effective in elevating PDT-mediated tumor cure rates even when injected peritumorally immediately after PDT. Edelfosine used before PDT was ineffective as adjuvant with all tumor models. The study findings provide proof-in-principle for use of cancer lipids with tumor PDT. Full article

(This article belongs to the Special Issue Photodynamic Therapy in Cancer: Principles, State of the Art, and Future Directions)

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14 pages, 2553 KiB

Open AccessEditor’s ChoiceArticle

Improved Therapeutic Efficacy of MT102, a New Anti-Inflammatory Agent, via a Self-Microemulsifying Drug Delivery System, in Ulcerative Colitis Mice

by Kshitis Chandra Baral, Sang Hoon Lee, Jae Geun Song, Seong Hoon Jeong and Hyo-Kyung Han

Pharmaceutics 2023, 15(12), 2720; https://doi.org/10.3390/pharmaceutics15122720 - 2 Dec 2023

Viewed by 1223

Abstract

MT-102 is a new anti-inflammatory agent derived from Juglans mandshurica and Isatis indigotica. Its therapeutic potential is hindered by low aqueous solubility, impacting its in vivo efficacy. Therefore, this study aimed to develop a self-microemulsifying drug delivery system (SMEDDS) for MT-102 to [...] Read more.

MT-102 is a new anti-inflammatory agent derived from Juglans mandshurica and Isatis indigotica. Its therapeutic potential is hindered by low aqueous solubility, impacting its in vivo efficacy. Therefore, this study aimed to develop a self-microemulsifying drug delivery system (SMEDDS) for MT-102 to enhance its oral efficacy in treating ulcerative colitis. Solubility assessment in different oils, surfactants, and cosurfactants led to a SMEDDS formulation of MT-102 using Capmul MCM, Tween 80, and propylene glycol. Based on a pseudoternary phase diagram, the optimal SMEDDS composition was selected, which consisted of 15% Capmul MCM, 42.5% Tween 80, and 42.5% propylene glycol. The resulting optimized SMEDDS (SMEDDS-F1) exhibited a narrow size distribution (177.5 ± 2.80 nm) and high indirubin content (275 ± 5.58 µg/g, a biomarker). Across an acidic to neutral pH range, SMEDDS-F1 showed rapid and extensive indirubin release, with dissolution rates approximately 15-fold higher than pure MT-102. Furthermore, oral administration of SMEDDS-F1 effectively mitigated inflammatory progression and symptoms in a mouse model of ulcerative colitis, whereas pure MT-102 was ineffective. SMEDDS-F1 minimized body weight loss (less than 5%) without any significant change in colon length and the morphology of colonic tissues, compared to those of the healthy control group. In addition, oral administration of SMEDDS-F1 significantly inhibited the secretion of pro-inflammatory cytokines such as IL-6 and TNF-α. In conclusion, the SMEDDS-F1 formulation employing Capmul MCM, Tween 80, and propylene glycol (15:42.5:42.5, w/w) enhances the solubility and therapeutic efficacy of MT-102. Full article

(This article belongs to the Collection Advanced Pharmaceutical Science and Technology in Korea)

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20 pages, 4226 KiB

Open AccessEditor’s ChoiceReview

Natural Chalcones and Derivatives in Colon Cancer: Pre-Clinical Challenges and the Promise of Chalcone-Based Nanoparticles

by Soufyane Hba, Suzan Ghaddar, Hicham Wahnou, Aline Pinon, Riad El Kebbaj, Christelle Pouget, Vincent Sol, Bertrand Liagre, Mounia Oudghiri and Youness Limami

Pharmaceutics 2023, 15(12), 2718; https://doi.org/10.3390/pharmaceutics15122718 - 1 Dec 2023

Cited by 2 | Viewed by 1577

Abstract

Colon cancer poses a complex and substantial global health challenge, necessitating innovative therapeutic approaches. Chalcones, a versatile class of compounds with diverse pharmacological properties, have emerged as promising candidates for addressing colon cancer. Their ability to modulate pivotal signaling pathways in the development [...] Read more.

Colon cancer poses a complex and substantial global health challenge, necessitating innovative therapeutic approaches. Chalcones, a versatile class of compounds with diverse pharmacological properties, have emerged as promising candidates for addressing colon cancer. Their ability to modulate pivotal signaling pathways in the development and progression of colon cancer makes them invaluable as targeted therapeutics. Nevertheless, it is crucial to recognize that although chalcones exhibit promise, further pre-clinical studies are required to validate their efficacy and safety. The journey toward effective colon cancer treatment is multifaceted, involving considerations such as optimizing the sequencing of therapeutic agents, comprehending the resistance mechanisms, and exploring combination therapies incorporating chalcones. Furthermore, the integration of nanoparticle-based drug delivery systems presents a novel avenue for enhancing the effectiveness of chalcones in colon cancer treatment. This review delves into the mechanisms of action of natural chalcones and some derivatives. It highlights the challenges associated with their use in pre-clinical studies, while also underscoring the advantages of employing chalcone-based nanoparticles for the treatment of colon cancer. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies, 3rd Edition)

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20 pages, 1049 KiB

Open AccessEditor’s ChoiceReview

Recent Advancements in the Development of Nanocarriers for Mucosal Drug Delivery Systems to Control Oral Absorption

by Hideyuki Sato, Kohei Yamada, Masateru Miyake and Satomi Onoue

Pharmaceutics 2023, 15(12), 2708; https://doi.org/10.3390/pharmaceutics15122708 - 30 Nov 2023

Cited by 4 | Viewed by 1430

Abstract

Oral administration of active pharmaceutical ingredients is desirable because it is easy, safe, painless, and can be performed by patients, resulting in good medication adherence. The mucus layer in the gastrointestinal (GI) tract generally acts as a barrier to protect the epithelial membrane [...] Read more.

Oral administration of active pharmaceutical ingredients is desirable because it is easy, safe, painless, and can be performed by patients, resulting in good medication adherence. The mucus layer in the gastrointestinal (GI) tract generally acts as a barrier to protect the epithelial membrane from foreign substances; however, in the absorption process after oral administration, it can also disturb effective drug absorption by trapping it in the biological sieve structured by mucin, a major component of mucus, and eliminating it by mucus turnover. Recently, functional nanocarriers (NCs) have attracted much attention due to their immense potential and effectiveness in the field of oral drug delivery. Among them, NCs with mucopenetrating and mucoadhesive properties are promising dosage options for controlling drug absorption from the GI tracts. Mucopenetrating and mucoadhesive NCs can rapidly deliver encapsulated drugs to the absorption site and/or prolong the residence time of NCs close to the absorption membrane, providing better medications than conventional approaches. The surface characteristics of NCs are important factors that determine their functionality, owing to the formation of various kinds of interactions between the particle surface and mucosal components. Thus, a deeper understanding of surface modifications on the biopharmaceutical characteristics of NCs is necessary to develop the appropriate mucosal drug delivery systems (mDDS) for the treatment of target diseases. This review summarizes the basic information and functions of the mucosal layer, highlights the recent progress in designing functional NCs for mDDS, and discusses their performance in the GI tract. Full article

(This article belongs to the Special Issue The Latest Technology for the Prediction and Improvement of Drug Absorption)

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18 pages, 3311 KiB

Open AccessEditor’s ChoiceArticle

Temoporfin-Conjugated Upconversion Nanoparticles for NIR-Induced Photodynamic Therapy: Studies with Pancreatic Adenocarcinoma Cells In Vitro and In Vivo

by Oleksandr Shapoval, David Větvička, Vitalii Patsula, Hana Engstová, Olga Kočková, Magdalena Konefał, Martina Kabešová and Daniel Horák

Pharmaceutics 2023, 15(12), 2694; https://doi.org/10.3390/pharmaceutics15122694 - 28 Nov 2023

Cited by 3 | Viewed by 1292

Abstract

Upconverting nanoparticles are interesting materials that have the potential for use in many applications ranging from solar energy harvesting to biosensing, light-triggered drug delivery, and photodynamic therapy (PDT). One of the main requirements for the particles is their surface modification, in our case [...] Read more.

Upconverting nanoparticles are interesting materials that have the potential for use in many applications ranging from solar energy harvesting to biosensing, light-triggered drug delivery, and photodynamic therapy (PDT). One of the main requirements for the particles is their surface modification, in our case using poly(methyl vinyl ether-alt-maleic acid) (PMVEMA) and temoporfin (THPC) photosensitizer to ensure the colloidal and chemical stability of the particles in aqueous media and the formation of singlet oxygen after NIR irradiation, respectively. Codoping of Fe²⁺, Yb³⁺, and Er³⁺ ions in the NaYF₄ host induced upconversion emission of particles in the red region, which is dominant for achieving direct excitation of THPC. Novel monodisperse PMVEMA-coated upconversion NaYF₄:Yb³⁺,Er³⁺,Fe²⁺ nanoparticles (UCNPs) with chemically bonded THPC were found to efficiently transfer energy and generate singlet oxygen. The cytotoxicity of the UCNPs was determined in the human pancreatic adenocarcinoma cell lines Capan-2, PANC-01, and PA-TU-8902. In vitro data demonstrated enhanced uptake of UCNP@PMVEMA-THPC particles by rat INS-1E insulinoma cells, followed by significant cell destruction after excitation with a 980 nm laser. Intratumoral administration of these nanoconjugates into a mouse model of human pancreatic adenocarcinoma caused extensive necrosis at the tumor site, followed by tumor suppression after NIR-induced PDT. In vitro and in vivo results thus suggest that this nanoconjugate is a promising candidate for NIR-induced PDT of cancer. Full article

(This article belongs to the Special Issue Advanced Nanopharmaceutics for Anticancer Therapy)

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24 pages, 5567 KiB

Open AccessEditor’s ChoiceArticle

Study of the Molecular Architectures of 2-(4-Chlorophenyl)-5-(pyrrolidin-1-yl)-2H-1,2,3-triazole-4-carboxylic Acid Using Their Vibrational Spectra, Quantum Chemical Calculations and Molecular Docking with MMP-2 Receptor

by Mauricio Alcolea Palafox, Nataliya P. Belskaya and Irena P. Kostova

Pharmaceutics 2023, 15(12), 2686; https://doi.org/10.3390/pharmaceutics15122686 - 27 Nov 2023

Cited by 1 | Viewed by 1145

Abstract

1,2,3-triazole skeleton is a valuable building block for the discovery of new promising anticancer agents. In the present work, the molecular structure of the synthesized anticancer drug 2-(4-chlorophenyl)-5-(pyrrolidin-1-yl)-2H-1,2,3-triazole-4-carboxylic acid (1b) and its anionic form (2b) was characterized [...] Read more.

1,2,3-triazole skeleton is a valuable building block for the discovery of new promising anticancer agents. In the present work, the molecular structure of the synthesized anticancer drug 2-(4-chlorophenyl)-5-(pyrrolidin-1-yl)-2H-1,2,3-triazole-4-carboxylic acid (1b) and its anionic form (2b) was characterized by means of the B3LYP, M06-2X and MP2 quantum chemical methods, optimizing their monomer, cyclic dimer and stacking forms using the Gaussian16 program package. The molecular structure was found to be slightly out of plane. The good agreement between the IR and Raman bands experimentally observed in the solid state with those calculated theoretically confirms the synthesized structures. All of the bands were accurately assigned according to functional calculations (DFT) in the monomer and dimer forms, together with the polynomic scaling equation procedure (PSE). Therefore, the effect of the substituents on the triazole ring and the effect of the chlorine atom on the molecular structure and on the vibrational spectra were evaluated through comparison with its non-substituted form. Through molecular docking calculations, it was evaluated as to how molecule 1b interacts with few amino acids of the MMP-2 metalloproteinase receptor, using Sybyl-X 2.0 software. Thus, the relevance of triazole scaffolds in established hydrogen bond-type interactions was demonstrated. Full article

(This article belongs to the Topic New Compounds Discovery and Development in Medicine — Advances in Research on Potential Therapeutic Agents and Drug Candidates)

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17 pages, 656 KiB

Open AccessEditor’s ChoiceReview

Intradermal Delivery of Naked mRNA Vaccines via Iontophoresis

by Mahadi Hasan, Anowara Khatun and Kentaro Kogure

Pharmaceutics 2023, 15(12), 2678; https://doi.org/10.3390/pharmaceutics15122678 - 26 Nov 2023

Cited by 2 | Viewed by 2024

Abstract

Messenger RNA (mRNA) vaccines against infectious diseases and for anticancer immunotherapy have garnered considerable attention. Currently, mRNA vaccines encapsulated in lipid nanoparticles are administrated via intramuscular injection using a needle. However, such administration is associated with pain, needle phobia, and lack of patient [...] Read more.

Messenger RNA (mRNA) vaccines against infectious diseases and for anticancer immunotherapy have garnered considerable attention. Currently, mRNA vaccines encapsulated in lipid nanoparticles are administrated via intramuscular injection using a needle. However, such administration is associated with pain, needle phobia, and lack of patient compliance. Furthermore, side effects such as fever and anaphylaxis associated with the lipid nanoparticle components are also serious problems. Therefore, noninvasive, painless administration of mRNA vaccines that do not contain other problematic components is highly desirable. Antigen-presenting cells reside in the epidermis and dermis, making the skin an attractive vaccination site. Iontophoresis (ItP) uses weak electric current applied to the skin surface and offers a noninvasive permeation technology that enables intradermal delivery of hydrophilic and ionic substances. ItP-mediated intradermal delivery of biological macromolecules has also been studied. Herein, we review the literature on the use of ItP technology for intradermal delivery of naked mRNA vaccines which is expected to overcome the challenges associated with mRNA vaccination. In addition to the physical mechanism, we discuss novel biological mechanisms of iontophoresis, particularly ItP-mediated opening of the skin barriers and the intracellular uptake pathway, and how the combined mechanisms can allow for effective intradermal delivery of mRNA vaccines. Full article

(This article belongs to the Special Issue Advances in the Development of mRNA Medicines and mRNA Vaccines)

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28 pages, 7654 KiB

Open AccessEditor’s ChoiceReview

Topoisomeric Membrane-Active Peptides: A Review of the Last Two Decades

by Adam Carrera-Aubesart, Maria Gallo, Sira Defaus, Toni Todorovski and David Andreu

Pharmaceutics 2023, 15(10), 2451; https://doi.org/10.3390/pharmaceutics15102451 - 12 Oct 2023

Cited by 2 | Viewed by 1267

Abstract

In recent decades, bioactive peptides have been gaining recognition in various biomedical areas, such as intracellular drug delivery (cell-penetrating peptides, CPPs) or anti-infective action (antimicrobial peptides, AMPs), closely associated to their distinct mode of interaction with biological membranes. Exploiting the interaction of membrane-active [...] Read more.

In recent decades, bioactive peptides have been gaining recognition in various biomedical areas, such as intracellular drug delivery (cell-penetrating peptides, CPPs) or anti-infective action (antimicrobial peptides, AMPs), closely associated to their distinct mode of interaction with biological membranes. Exploiting the interaction of membrane-active peptides with diverse targets (healthy, tumoral, bacterial or parasitic cell membranes) is opening encouraging prospects for peptides in therapeutics. However, ordinary peptides formed by L-amino acids are easily decomposed by proteases in biological fluids. One way to sidestep this limitation is to use topoisomers, namely versions of the peptide made up of D-amino acids in either canonic (enantio) or inverted (retroenantio) sequence. Rearranging peptide sequences in this fashion provides a certain degree of native structure mimicry that, in appropriate contexts, may deliver desirable biological activity while avoiding protease degradation. In this review, we will focus on recent accounts of membrane-active topoisomeric peptides with therapeutic applications as CPP drug delivery vectors, or as antimicrobial and anticancer candidates. We will also discuss the most common modes of interaction of these peptides with their membrane targets. Full article

(This article belongs to the Special Issue State of the Art of Membrane Active Peptides)

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14 pages, 1226 KiB

Open AccessEditor’s ChoiceReview

IL-17 Inhibition: A Valid Therapeutic Strategy in the Management of Hidradenitis Suppurativa

by Dalma Malvaso, Laura Calabrese, Andrea Chiricozzi, Flaminia Antonelli, Giulia Coscarella, Pietro Rubegni and Ketty Peris

Pharmaceutics 2023, 15(10), 2450; https://doi.org/10.3390/pharmaceutics15102450 - 11 Oct 2023

Cited by 4 | Viewed by 2696

Abstract

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with a significant negative impact on the quality of life of patients. To date, the therapeutic landscape for the management of the disease has been extremely limited, resulting in a profound unmet need. Indeed, [...] Read more.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with a significant negative impact on the quality of life of patients. To date, the therapeutic landscape for the management of the disease has been extremely limited, resulting in a profound unmet need. Indeed, adalimumab, an anti-tumor necrosis factor (TNF)-α monoclonal antibody, is the only approved biologic agent for HS, obtaining a therapeutic response in only 50% of HS patients. Numerous clinical trials are currently ongoing to test novel therapeutic targets in HS. The IL-17-mediated cascade is the target of several biologic agents that have shown efficacy and safety in treating moderate-to-severe HS. Both bimekizumab and secukinumab, targeting IL-17 in different manners, have successfully completed phase III trials with promising results; the latter has recently been approved by EMA for the treatment of HS. The aim of this review is to summarize the current state of knowledge concerning the relevant role of IL-17 in HS pathogenesis, highlighting the key clinical evidence of anti-IL-17 agents in the treatment of this disease. Full article

(This article belongs to the Special Issue New and Emerging Targeted Topical and Systemic Drugs for Immunemediated Cutaneous Diseases)

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19 pages, 2126 KiB

Open AccessEditor’s ChoiceReview

Strategies for Drug Delivery into the Brain: A Review on Adenosine Receptors Modulation for Central Nervous System Diseases Therapy

by Mercedes Fernandez, Manuela Nigro, Alessia Travagli, Silvia Pasquini, Fabrizio Vincenzi, Katia Varani, Pier Andrea Borea, Stefania Merighi and Stefania Gessi

Pharmaceutics 2023, 15(10), 2441; https://doi.org/10.3390/pharmaceutics15102441 - 10 Oct 2023

Cited by 1 | Viewed by 2224

Abstract

The blood–brain barrier (BBB) is a biological barrier that protects the central nervous system (CNS) by ensuring an appropriate microenvironment. Brain microvascular endothelial cells (ECs) control the passage of molecules from blood to brain tissue and regulate their concentration-versus-time profiles to guarantee proper [...] Read more.

The blood–brain barrier (BBB) is a biological barrier that protects the central nervous system (CNS) by ensuring an appropriate microenvironment. Brain microvascular endothelial cells (ECs) control the passage of molecules from blood to brain tissue and regulate their concentration-versus-time profiles to guarantee proper neuronal activity, angiogenesis and neurogenesis, as well as to prevent the entry of immune cells into the brain. However, the BBB also restricts the penetration of drugs, thus presenting a challenge in the development of therapeutics for CNS diseases. On the other hand, adenosine, an endogenous purine-based nucleoside that is expressed in most body tissues, regulates different body functions by acting through its G-protein-coupled receptors (A1, A2A, A2B and A3). Adenosine receptors (ARs) are thus considered potential drug targets for treating different metabolic, inflammatory and neurological diseases. In the CNS, A1 and A2A are expressed by astrocytes, oligodendrocytes, neurons, immune cells and ECs. Moreover, adenosine, by acting locally through its receptors A1 and/or A2A, may modulate BBB permeability, and this effect is potentiated when both receptors are simultaneously activated. This review showcases in vivo and in vitro evidence supporting AR signaling as a candidate for modifying endothelial barrier permeability in the treatment of CNS disorders. Full article

(This article belongs to the Special Issue Roles of Transporters and Receptors in Drug Delivery to the Brain in Health and Disease)

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18 pages, 3570 KiB

Open AccessEditor’s ChoiceReview

Recent Progress in Diatom Biosilica: A Natural Nanoporous Silica Material as Sustained Release Carrier

by Hayeon Lim, Yoseph Seo, Daeryul Kwon, Sunggu Kang, Jiyun Yu, Hyunjun Park, Sang Deuk Lee and Taek Lee

Pharmaceutics 2023, 15(10), 2434; https://doi.org/10.3390/pharmaceutics15102434 - 9 Oct 2023

Cited by 3 | Viewed by 1734

Abstract

A drug delivery system (DDS) is a useful technology that efficiently delivers a target drug to a patient’s specific diseased tissue with minimal side effects. DDS is a convergence of several areas of study, comprising pharmacy, medicine, biotechnology, and chemistry fields. In the [...] Read more.

A drug delivery system (DDS) is a useful technology that efficiently delivers a target drug to a patient’s specific diseased tissue with minimal side effects. DDS is a convergence of several areas of study, comprising pharmacy, medicine, biotechnology, and chemistry fields. In the traditional pharmacological concept, developing drugs for disease treatment has been the primary research field of pharmacology. The significance of DDS in delivering drugs with optimal formulation to target areas to increase bioavailability and minimize side effects has been recently highlighted. In addition, since the burst release found in various DDS platforms can reduce drug delivery efficiency due to unpredictable drug loss, many recent DDS studies have focused on developing carriers with a sustained release. Among various drug carriers, mesoporous silica DDS (MS-DDS) is applied to various drug administration routes, based on its sustained releases, nanosized porous structures, and excellent solubility for poorly soluble drugs. However, the synthesized MS-DDS has caused complications such as toxicity in the body, long-term accumulation, and poor excretion ability owing to acid treatment-centered manufacturing methods. Therefore, biosilica obtained from diatoms, as a natural MS-DDS, has recently emerged as an alternative to synthesized MS-DDS. This natural silica carrier is an optimal DDS platform because culturing diatoms is easy, and the silica can be separated from diatoms using a simple treatment. In this review, we discuss the manufacturing methods and applications to various disease models based on the advantages of biosilica. Full article

(This article belongs to the Special Issue Functionalized Polymers in Drug Delivery)

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17 pages, 3858 KiB

Open AccessEditor’s ChoiceArticle

Selection of Excipients for the Preparation of Vancomycin-Loaded Poly(D,L-lactide-co-glycolide) Microparticles with Extended Release by Emulsion Spray Drying

by Ana Jurić Simčić, Iva Erak, Biserka Cetina Čižmek, Anita Hafner and Jelena Filipović-Grčić

Pharmaceutics 2023, 15(10), 2438; https://doi.org/10.3390/pharmaceutics15102438 - 9 Oct 2023

Cited by 1 | Viewed by 1086

Abstract

The aim of this study was to relate the composition of the W/O emulsion used as a starting fluid in the spray-drying process to the quality of the dry polymer particles obtained in terms of physical–chemical properties, compatibility and drug release performance. Four [...] Read more.

The aim of this study was to relate the composition of the W/O emulsion used as a starting fluid in the spray-drying process to the quality of the dry polymer particles obtained in terms of physical–chemical properties, compatibility and drug release performance. Four W/O emulsions containing vancomycin hydrochloride (VAN), an encapsulating PLGA polymer and Poloxamer^® 407, chitosan and/or sorbitan monooleate as stabilisers were spray-dried using an ultrasonic atomising nozzle. The microparticles obtained were micron-sized, with a volume mean diameter between 43.2 ± 0.3 and 64.0 ± 12.6 µm, and spherical with a mostly smooth, non-porous surface and with high drug loading (between 14.5 ± 0.6 and 17.1 ± 1.9% w/w). All formulations showed a prolonged and biphasic VAN release profile, with diffusion being the primary release mechanism. Microparticles prepared from the emulsions with Poloxamer^® 407 and sorbitan monooleate released VAN rapidly and completely within one day. The release of VAN from microparticles prepared from the emulsion without additives or with chitosan in the inner aqueous phase was significantly decreased; after four days, a cumulative release of 65% and 61%, respectively, was achieved. Microparticles with encapsulated chitosan had the largest mean particle diameter and the slowest release of VAN. Full article

(This article belongs to the Section Drug Delivery and Controlled Release)

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11 pages, 1502 KiB

Open AccessEditor’s ChoiceArticle

Systems Biology and Peptide Engineering to Overcome Absorption Barriers for Oral Peptide Delivery: Dosage Form Optimization Case Study Preceding Clinical Translation

by Puneet Tyagi, Chandresh Patel, Kimberly Gibson, Fiona MacDougall, Sergei Y. Pechenov, Sarah Will, Jefferson Revell, Yue Huang, Anton I. Rosenbaum, Kemal Balic, Umar Maharoof, Joseph Grimsby and J. Anand Subramony

Pharmaceutics 2023, 15(10), 2436; https://doi.org/10.3390/pharmaceutics15102436 - 9 Oct 2023

Viewed by 1706

Abstract

Oral delivery of peptides and biological molecules promises significant benefits to patients as an alternative to daily injections, but the development of these formulations is challenging due to their low bioavailability and high pharmacokinetic variability. Our earlier work focused on the discovery of [...] Read more.

Oral delivery of peptides and biological molecules promises significant benefits to patients as an alternative to daily injections, but the development of these formulations is challenging due to their low bioavailability and high pharmacokinetic variability. Our earlier work focused on the discovery of MEDI7219, a stabilized, lipidated, glucagon-like peptide 1 agonist peptide, and the selection of sodium chenodeoxycholate (Na CDC) and propyl gallate (PG) as permeation enhancer combinations. We hereby describe the development of the MEDI7219 tablet formulations and composition optimization via in vivo studies in dogs. We designed the MEDI7219 immediate-release tablets with the permeation enhancers Na CDC and PG. Immediate-release tablets were coated with an enteric coating that dissolves at pH ≥ 5.5 to target the upper duodenal region of the gastrointestinal tract and sustained-release tablets with a Carbopol bioadhesive polymer were coated with an enteric coating that dissolves at pH ≥ 7.0 to provide a longer presence at the absorption site in the gastrointestinal tract. In addition to immediate- and enteric-coated formulations, we also tested a proprietary delayed release erodible barrier layer tablet (OralogiK^TM) to deliver the payload to the target site in the gastrointestinal tract. The design of tablet dosage forms based on the optimization of formulations resulted in up to 10.1% absolute oral bioavailability in dogs with variability as low as 26% for MEDI7219, paving the way for its clinical development. Full article

(This article belongs to the Special Issue New Technology for Prolonged Drug Release)

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50 pages, 8242 KiB

Open AccessEditor’s ChoiceReview

Pediatric Drug Development: Reviewing Challenges and Opportunities by Tracking Innovative Therapies

by Cátia Domingues, Ivana Jarak, Francisco Veiga, Marília Dourado and Ana Figueiras

Pharmaceutics 2023, 15(10), 2431; https://doi.org/10.3390/pharmaceutics15102431 - 6 Oct 2023

Cited by 5 | Viewed by 5615

Abstract

The paradigm of pediatric drug development has been evolving in a “carrot-and-stick”-based tactic to address population-specific issues. However, the off-label prescription of adult medicines to pediatric patients remains a feature of clinical practice, which may compromise the age-appropriate evaluation of treatments. Therefore, the [...] Read more.

The paradigm of pediatric drug development has been evolving in a “carrot-and-stick”-based tactic to address population-specific issues. However, the off-label prescription of adult medicines to pediatric patients remains a feature of clinical practice, which may compromise the age-appropriate evaluation of treatments. Therefore, the United States and the European Pediatric Formulation Initiative have recommended applying nanotechnology-based delivery systems to tackle some of these challenges, particularly applying inorganic, polymeric, and lipid-based nanoparticles. Connected with these, advanced therapy medicinal products (ATMPs) have also been highlighted, with optimistic perspectives for the pediatric population. Despite the results achieved using these innovative therapies, a workforce that congregates pediatric patients and/or caregivers, healthcare stakeholders, drug developers, and physicians continues to be of utmost relevance to promote standardized guidelines for pediatric drug development, enabling a fast lab-to-clinical translation. Therefore, taking into consideration the significance of this topic, this work aims to compile the current landscape of pediatric drug development by (1) outlining the historic regulatory panorama, (2) summarizing the challenges in the development of pediatric drug formulation, and (3) delineating the advantages/disadvantages of using innovative approaches, such as nanomedicines and ATMPs in pediatrics. Moreover, some attention will be given to the role of pharmaceutical technologists and developers in conceiving pediatric medicines. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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19 pages, 3214 KiB

Open AccessEditor’s ChoiceArticle

Systemic Dendrimer-Peptide Therapies for Wet Age-Related Macular Degeneration

by Tony Wu, Chang Liu and Rangaramanujam M. Kannan

Pharmaceutics 2023, 15(10), 2428; https://doi.org/10.3390/pharmaceutics15102428 - 5 Oct 2023

Cited by 1 | Viewed by 1222

Abstract

Wet age-related macular degeneration (AMD) is an end-stage event in a complex pathogenesis of macular degeneration, involving the abnormal growth of blood vessels at the retinal pigment epithelium driven by vascular endothelial growth factor (VEGF). Current therapies seek to interrupt VEGF signaling to [...] Read more.

Wet age-related macular degeneration (AMD) is an end-stage event in a complex pathogenesis of macular degeneration, involving the abnormal growth of blood vessels at the retinal pigment epithelium driven by vascular endothelial growth factor (VEGF). Current therapies seek to interrupt VEGF signaling to halt the progress of neovascularization, but a significant patient population is not responsive. New treatment modalities such as integrin-binding peptides (risuteganib/Luminate/ALG-1001) are being explored to address this clinical need but these treatments necessitate the use of intravitreal injections (IVT), which carries risks of complications and restricts its availability in less-developed countries. Successful systemic delivery of peptide-based therapeutics must overcome obstacles such as degradation by proteinases in circulation and off-target binding. In this work, we present a novel dendrimer-integrin-binding peptide (D-ALG) synthesized with a noncleavable, “clickable” linker. In vitro, D-ALG protected the peptide payload from enzymatic degradation for up to 1.5 h (~90% of the compound remained intact) in a high concentration of proteinase (2 mg/mL) whereas ~90% of free ALG-1001 was degraded in the same period. Further, dendrimer conjugation preserved the antiangiogenic activity of ALG-1001 in vitro with significant reductions in endothelial vessel network formation compared to untreated controls. In vivo, direct intravitreal injections of ALG-1001 and D-ALG produced reductions in the CNV lesion area but in systemically dosed animals, only D-ALG produced significant reductions of CNV lesion area at 14 days. Imaging data suggested that the difference in efficacy may be due to more D-ALG remaining in the target area than ALG-1001 after administration. The results presented here offer a clinically relevant route for peptide therapeutics by addressing the major obstacles that these therapies face in delivery. Full article

(This article belongs to the Special Issue Dendrimers: A Themed Issue in Honor of Professor Donald A. Tomalia on the Occasion of His 85th Birthday for His Outstanding Achievements in Advancing the Field of Dendrimers)

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23 pages, 4805 KiB

Open AccessEditor’s ChoiceArticle

Development, Characterization and Pharmacological Evaluation of Cannabidiol-Loaded Long Circulating Niosomes

by Viliana Gugleva, Katerina Ahchiyska, Dilyana Georgieva, Rositsa Mihaylova, Spiro Konstantinov, Erik Dimitrov, Natalia Toncheva-Moncheva, Stanislav Rangelov, Aleksander Forys, Barbara Trzebicka and Denitsa Momekova

Pharmaceutics 2023, 15(10), 2414; https://doi.org/10.3390/pharmaceutics15102414 - 3 Oct 2023

Cited by 1 | Viewed by 1604

Abstract

Cannabidiol (CBD) is a promising drug candidate with pleiotropic pharmacological activity, whose low aqueous solubility and unfavorable pharmacokinetics have presented obstacles to its full clinical implementation. The rational design of nanocarriers, including niosomes for CBD encapsulation, can provide a plausible approach to overcoming [...] Read more.

Cannabidiol (CBD) is a promising drug candidate with pleiotropic pharmacological activity, whose low aqueous solubility and unfavorable pharmacokinetics have presented obstacles to its full clinical implementation. The rational design of nanocarriers, including niosomes for CBD encapsulation, can provide a plausible approach to overcoming these limitations. The present study is focused on exploring the feasibility of copolymer-modified niosomes as platforms for systemic delivery of CBD. To confer steric stabilization, the niosomal membranes were grafted with newly synthesized amphiphilic linear or star-shaped 3- and 4-arm star-shaped copolymers based on polyglycidol (PG) and poly(ε-caprolactone) (PCL) blocks. The niosomes were prepared by film hydration method and were characterized by DLS, cryo-TEM, encapsulation efficacy, and in vitro release. Free and formulated cannabidiol were further investigated for cytotoxicity and pro-apoptotic and anti-inflammatory activities in vitro in three human tumor cell lines. The optimal formulation, based on Tween 60:Span60:Chol (3.5:3.5:3 molar ration) modified with 2.5 mol% star-shaped 3-arm copolymer, is characterized by a size of 235 nm, high encapsulation of CBD (94%), and controlled release properties. Niosomal cannabidiol retained the antineoplastic activity of the free agent, but noteworthy superior apoptogenic and inflammatory biomarker-modulating effects were established at equieffective exposure vs. the free drug. Specific alterations in key signaling molecules, implicated in programmed cell death, cancer cell biology, and inflammation, were recorded with the niosomal formulations. Full article

(This article belongs to the Special Issue Self-Assembled Amphiphilic Copolymers in Drug Delivery)

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30 pages, 7651 KiB

Open AccessEditor’s ChoiceArticle

Mucoadhesive Alginate/Pectin Films Crosslinked by Calcium Carbonate as Carriers of a Model Antifungal Drug—Posaconazole

by Marta Szekalska, Anna Czajkowska-Kośnik, Bartosz Maciejewski, Iwona Misztalewska-Turkowicz, Agnieszka Zofia Wilczewska, Jurga Bernatoniene and Katarzyna Winnicka

Pharmaceutics 2023, 15(10), 2415; https://doi.org/10.3390/pharmaceutics15102415 - 3 Oct 2023

Cited by 1 | Viewed by 1419

Abstract

The mucosal membrane of the oral cavity, due to its unique structure and availability, constitutes an appropriate site for the delivery of drugs, both with local and systemic effects. Mucoadhesive buccal films are drug dosage forms that due to their convenience of application, [...] Read more.

The mucosal membrane of the oral cavity, due to its unique structure and availability, constitutes an appropriate site for the delivery of drugs, both with local and systemic effects. Mucoadhesive buccal films are drug dosage forms that due to their convenience of application, flexibility and size, are characterized by patients’ compliance. Sodium alginate and pectin are natural polymers from the polysaccharides group, with mucoadhesive properties, that are widely applied to obtain buccal films. However, their hydrophilic nature and poor water resistance limit their application in sustained drug release formulations. Hence, the aim of this investigation was to design alginate/pectin buccal films by a one-step crosslinking technique—with the application of calcium carbonate. This technique was applied to prepare crosslinked alginate and alginate/pectin mucoadhesive films with a model antifungal drug—posaconazole. The obtained formulations were evaluated for the impact of crosslinking and pectin’s presence on their pharmaceutical, mucoadhesive, mechanical and physicochemical properties. Additionally, the antifungal activity of the prepared films against Candida spp. was evaluated. It was shown that pectin’s presence in the formulations improved flexibility, mucoadhesion and antifungal activity. The crosslinking process reduced mucoadhesiveness and antifungal activity but significantly enhanced the mechanical properties and stability and enabled prolonged drug release. Full article

(This article belongs to the Special Issue New Technology for Prolonged Drug Release, 2nd Edition)

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17 pages, 12498 KiB

Open AccessEditor’s ChoiceArticle

Lipid-Coated Polymeric Nanoparticles for the Photodynamic Therapy of Head and Neck Squamous Cell Carcinomas

by Valeri Roschenko, Abdallah M. Ayoub, Konrad Engelhardt, Jens Schäfer, Muhammad Umair Amin, Eduard Preis, Robert Mandic and Udo Bakowsky

Pharmaceutics 2023, 15(10), 2412; https://doi.org/10.3390/pharmaceutics15102412 - 2 Oct 2023

Viewed by 1339

Abstract

Next to alcohol and tobacco abuse, infection with human papillomaviruses (HPVs) is a major risk factor for developing head and neck squamous cell carcinomas (HNSCCs), leading to 350,000 casualties worldwide each year. Limited therapy options and drug resistance raise the urge for alternative [...] Read more.

Next to alcohol and tobacco abuse, infection with human papillomaviruses (HPVs) is a major risk factor for developing head and neck squamous cell carcinomas (HNSCCs), leading to 350,000 casualties worldwide each year. Limited therapy options and drug resistance raise the urge for alternative methods such as photodynamic therapy (PDT), a minimally invasive procedure used to treat HNSCC and other cancers. We prepared lipid-coated polymeric nanoparticles encapsulating curcumin as the photosensitizer (CUR-LCNPs). The prepared CUR-LCNPs were in the nanometer range (153.37 ± 1.58 nm) and showed an encapsulation efficiency of 92.69 ± 0.03%. Proper lipid coating was visualized using atomic force microscopy (AFM). The CUR-LCNPs were tested in three HPV^pos and three HPV^neg HNSCC lines regarding their uptake capabilities and in vitro cell killing capacity, revealing a variable but highly significant tumor cell inhibiting effect in all tested HNSCC cell lines. No significant differences were detected between the HPV^pos and HPV^neg HNSCC groups (mean IC₅₀: (9.34 ± 4.73 µmol/L vs. 6.88 ± 1.03 µmol/L), suggesting CUR-LCNPs/PDT to be a promising therapeutic option for HNSCC patients independent of their HPV status. Full article

(This article belongs to the Special Issue Photodynamic Therapy: Rising Star in Pharmaceutical Applications)

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20 pages, 4517 KiB

Open AccessEditor’s ChoiceArticle

Efficacy of Apremilast Gels in Mouse Model of Imiquimod-Induced Psoriasis Skin Inflammation

by Marcelle Silva-Abreu, Lilian Sosa, Lupe Carolina Espinoza, María-José Fábrega, María J. Rodríguez-Lagunas, Mireia Mallandrich, Ana Cristina Calpena, María Luisa Garduño-Ramírez and María Rincón

Pharmaceutics 2023, 15(10), 2403; https://doi.org/10.3390/pharmaceutics15102403 - 29 Sep 2023

Cited by 2 | Viewed by 2238

Abstract

Apremilast (APM) is a novel drug for the treatment of psoriasis and psoriatic arthritis. APM is a phosphodiesterase 4 (PDE4) inhibitor, raising intracellular cAMP levels and thereby decreasing the inflammatory response by modulating the expression of TNF-α, IL-17, IL-23, and other inflammatory cytokines. [...] Read more.

Apremilast (APM) is a novel drug for the treatment of psoriasis and psoriatic arthritis. APM is a phosphodiesterase 4 (PDE4) inhibitor, raising intracellular cAMP levels and thereby decreasing the inflammatory response by modulating the expression of TNF-α, IL-17, IL-23, and other inflammatory cytokines. The goal of this study is to develop APM gels as a new pharmaceutical formulation for the treatment of topical psoriasis. APM was solubilized in Transcutol-P and incorporated into Pluronic F127, Sepigel, and carbomer bases at different proportions. All formulations were characterized physiochemically. A biopharmaceutical study (release profile) was performed, and ex vivo permeation was evaluated using a human skin model. A toxicity assay was carried out on the HaCaT cell line. A mouse model of imiquimod-induced psoriasis skin inflammation was carried out to determine its efficacy by histological analysis, RNA extraction, and RT-qPCR assays. APM gel formulations showed good physicochemical characteristics and a sustained release profile. There was no permeation of any gel measured through human skin, indicating a high retained amount of APM on the skin. Cell viability was greater than 80% at most dilution concentrations. APM gels treated the psoriasis mouse model, and it shows a reduction in the proinflammatory cytokines (IL-8, IL-17A, IL-17F, and IL-23). APM gels could be a new approach for the treatment of topical psoriasis. Full article

(This article belongs to the Section Drug Delivery and Controlled Release)

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50 pages, 10633 KiB

Open AccessEditor’s ChoiceReview

Resurgence and Repurposing of Antifungal Azoles by Transition Metal Coordination for Drug Discovery

by Youri Cortat and Fabio Zobi

Pharmaceutics 2023, 15(10), 2398; https://doi.org/10.3390/pharmaceutics15102398 - 28 Sep 2023

Cited by 1 | Viewed by 1099

Abstract

Coordination compounds featuring one or more antifungal azole (AA) ligands constitute an interesting family of candidate molecules, given their medicinal polyvalence and the viability of drug complexation as a strategy to improve and repurpose available medications. This review reports the work performed in [...] Read more.

Coordination compounds featuring one or more antifungal azole (AA) ligands constitute an interesting family of candidate molecules, given their medicinal polyvalence and the viability of drug complexation as a strategy to improve and repurpose available medications. This review reports the work performed in the field of coordination derivatives of AAs synthesized for medical purposes by discussing the corresponding publications and emphasizing the most promising compounds discovered so far. The resulting overview highlights the efficiency of AAs and their metallic species, as well as the potential still lying in this research area. Full article

(This article belongs to the Special Issue Novel Approaches in the Search for Active Compounds in Drug Discovery and Development)

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38 pages, 4754 KiB

Open AccessEditor’s ChoiceReview

Challenges in Permeability Assessment for Oral Drug Product Development

by Mirko Koziolek, Patrick Augustijns, Constantin Berger, Rodrigo Cristofoletti, David Dahlgren, Janneke Keemink, Pär Matsson, Fiona McCartney, Marco Metzger, Mario Mezler, Janis Niessen, James E. Polli, Maria Vertzoni, Werner Weitschies and Jennifer Dressman

Pharmaceutics 2023, 15(10), 2397; https://doi.org/10.3390/pharmaceutics15102397 - 28 Sep 2023

Cited by 3 | Viewed by 2879

Abstract

Drug permeation across the intestinal epithelium is a prerequisite for successful oral drug delivery. The increased interest in oral administration of peptides, as well as poorly soluble and poorly permeable compounds such as drugs for targeted protein degradation, have made permeability a key [...] Read more.

Drug permeation across the intestinal epithelium is a prerequisite for successful oral drug delivery. The increased interest in oral administration of peptides, as well as poorly soluble and poorly permeable compounds such as drugs for targeted protein degradation, have made permeability a key parameter in oral drug product development. This review describes the various in vitro, in silico and in vivo methodologies that are applied to determine drug permeability in the human gastrointestinal tract and identifies how they are applied in the different stages of drug development. The various methods used to predict, estimate or measure permeability values, ranging from in silico and in vitro methods all the way to studies in animals and humans, are discussed with regard to their advantages, limitations and applications. A special focus is put on novel techniques such as computational approaches, gut-on-chip models and human tissue-based models, where significant progress has been made in the last few years. In addition, the impact of permeability estimations on PK predictions in PBPK modeling, the degree to which excipients can affect drug permeability in clinical studies and the requirements for colonic drug absorption are addressed. Full article

(This article belongs to the Special Issue Recent Advances in Oral Biopharmaceutics)

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24 pages, 1792 KiB

Open AccessEditor’s ChoiceReview

Fc-Engineered Therapeutic Antibodies: Recent Advances and Future Directions

by Dalia T. Abdeldaim and Katharina Schindowski

Pharmaceutics 2023, 15(10), 2402; https://doi.org/10.3390/pharmaceutics15102402 - 28 Sep 2023

Cited by 8 | Viewed by 5699

Abstract

Monoclonal therapeutic antibodies have revolutionized the treatment of cancer and other diseases. Fc engineering aims to enhance the effector functions or half-life of therapeutic antibodies by modifying their Fc regions. Recent advances in the Fc engineering of modern therapeutic antibodies can be considered [...] Read more.

Monoclonal therapeutic antibodies have revolutionized the treatment of cancer and other diseases. Fc engineering aims to enhance the effector functions or half-life of therapeutic antibodies by modifying their Fc regions. Recent advances in the Fc engineering of modern therapeutic antibodies can be considered the next generation of antibody therapy. Various strategies are employed, including altering glycosylation patterns via glycoengineering and introducing mutations to the Fc region, thereby enhancing Fc receptor or complement interactions. Further, Fc engineering strategies enable the generation of bispecific IgG-based heterodimeric antibodies. As Fc engineering techniques continue to evolve, an expanding portfolio of Fc-engineered antibodies is advancing through clinical development, with several already approved for medical use. Despite the plethora of Fc-based mutations that have been analyzed in in vitro and in vivo models, we focus here in this review on the relevant Fc engineering strategies of approved therapeutic antibodies to finetune effector functions, to modify half-life and to stabilize asymmetric bispecific IgGs. Full article

(This article belongs to the Special Issue Recent Advances in Therapeutic Antibody)

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18 pages, 12805 KiB

Open AccessEditor’s ChoiceArticle

Mechanistic Insight into the Early Stages of Toroidal Pore Formation by the Antimicrobial Peptide Smp24

by Magnus Bertelsen, Melissa M. Lacey, Tim Nichol and Keith Miller

Pharmaceutics 2023, 15(10), 2399; https://doi.org/10.3390/pharmaceutics15102399 - 28 Sep 2023

Viewed by 1001

Abstract

The antimicrobial peptide Smp24, originally derived from the venom of Scorpio maurus palmatus, is a promising candidate for further drug development. However, before doing so, greater insight into the mechanism of action is needed to construct a reliable structure–activity relationship. The aim [...] Read more.

The antimicrobial peptide Smp24, originally derived from the venom of Scorpio maurus palmatus, is a promising candidate for further drug development. However, before doing so, greater insight into the mechanism of action is needed to construct a reliable structure–activity relationship. The aim of this study was to specifically investigate the critical early stages of peptide-induced membrane disruption. Single-channel current traces were obtained via planar patch-clamp electrophysiology, with multiple types of pore-forming events observed, unlike those expected from the traditional, more rigid mechanistic models. To better understand the molecular-level structures of the peptide-pore assemblies underlying these observed conductance events, molecular dynamics simulations were used to investigate the peptide structure and orientation both before and during pore formation. The transition of the peptides to transmembrane-like states within disordered toroidal pores occurred due to a peptide-induced bilayer-leaflet asymmetry, explaining why pore stabilization does not always follow pore nucleation in the experimental observations. To fully grasp the structure–activity relationship of antimicrobial peptides, a more nuanced view of the complex and dynamic mechanistic behaviour must be adopted. Full article

(This article belongs to the Special Issue State of the Art of Membrane Active Peptides)

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19 pages, 4893 KiB

Open AccessEditor’s ChoiceArticle

Ultrasound-Responsive Nanobubbles for Combined siRNA-Cerium Oxide Nanoparticle Delivery to Bone Cells

by Pedram Sotoudeh Bagha, Elayaraja Kolanthai, Fei Wei, Craig J. Neal, Udit Kumar, Gillian Braun, Melanie Coathup, Sudipta Seal and Mehdi Razavi

Pharmaceutics 2023, 15(10), 2393; https://doi.org/10.3390/pharmaceutics15102393 - 27 Sep 2023

Cited by 3 | Viewed by 1790

Abstract

This study aims to present an ultrasound-mediated nanobubble (NB)-based gene delivery system that could potentially be applied in the future to treat bone disorders such as osteoporosis. NBs are sensitive to ultrasound (US) and serve as a controlled-released carrier to deliver a mixture [...] Read more.

This study aims to present an ultrasound-mediated nanobubble (NB)-based gene delivery system that could potentially be applied in the future to treat bone disorders such as osteoporosis. NBs are sensitive to ultrasound (US) and serve as a controlled-released carrier to deliver a mixture of Cathepsin K (CTSK) siRNA and cerium oxide nanoparticles (CeNPs). This platform aimed to reduce bone resorption via downregulating CTSK expression in osteoclasts and enhance bone formation via the antioxidant and osteogenic properties of CeNPs. CeNPs were synthesized and characterized using transmission electron microscopy and X-ray photoelectron spectroscopy. The mixture of CTSK siRNA and CeNPs was adsorbed to the surface of NBs using a sonication method. The release profiles of CTSK siRNA and CeNPs labeled with a fluorescent tag molecule were measured after low-intensity pulsed ultrasound (LIPUS) stimulation using fluorescent spectroscopy. The maximum release of CTSK siRNA and the CeNPs for 1 mg/mL of NB-(CTSK siRNA + CeNPs) was obtained at 2.5 nM and 1 µg/mL, respectively, 3 days after LIPUS stimulation. Then, Alizarin Red Staining (ARS) was applied to human bone marrow-derived mesenchymal stem cells (hMSC) and tartrate-resistant acid phosphatase (TRAP) staining was applied to human osteoclast precursors (OCP) to evaluate osteogenic promotion and osteoclastogenic inhibition effects. A higher mineralization and a lower number of osteoclasts were quantified for NB-(CTSK siRNA + CeNPs) versus control +RANKL with ARS (p < 0.001) and TRAP-positive staining (p < 0.01). This study provides a method for the delivery of gene silencing siRNA and CeNPs using a US-sensitive NB system that could potentially be used in vivo and in the treatment of bone fractures and disorders such as osteoporosis. Full article

(This article belongs to the Section Drug Delivery and Controlled Release)

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12 pages, 1898 KiB

Open AccessEditor’s ChoiceArticle

Folate-Targeted Nanoliposomal Chemophototherapy

by Upendra Chitgupi, Yiru Qin, Sanjana Ghosh, Breandan Quinn, Kevin Carter, Xuedan He, Ulas Sunar and Jonathan F. Lovell

Pharmaceutics 2023, 15(10), 2385; https://doi.org/10.3390/pharmaceutics15102385 - 26 Sep 2023

Cited by 2 | Viewed by 1289

Abstract

Light-responsive liposomes have been developed for the on-demand release of drugs. However, efficient delivery of chemotherapeutic drugs to tumor for cancer theranostics remains a challenge. Herein, folic acid (FA), an established ligand for targeted drug delivery, was used to decorate light-sensitive porphyrin-phospholipid (PoP) [...] Read more.

Light-responsive liposomes have been developed for the on-demand release of drugs. However, efficient delivery of chemotherapeutic drugs to tumor for cancer theranostics remains a challenge. Herein, folic acid (FA), an established ligand for targeted drug delivery, was used to decorate light-sensitive porphyrin-phospholipid (PoP) liposomes, which were assessed for FA-targeted chemophototherapy (CPT). PoP liposomes and FA-conjugated PoP liposomes were loaded with Doxorubicin (Dox), and physical properties were characterized. In vitro, FA-PoP liposomes that were incubated with FA receptor-overexpressing human KB cancer cells showed increased uptake compared to non-targeted PoP liposomes. Dox and PoP contributed towards chemophototherapy (CPT) in vitro, and PoP and FA-PoP liposomes induced cell killing. In vivo, mice bearing subcutaneous KB tumors treated with PoP or FA-PoP liposomes loaded with Dox, followed by 665 nm laser treatment, had delayed tumor growth and improved survival. Dox delivery to tumors increased following laser irradiation for both PoP and FA-PoP liposomes. Thus, while Dox-FA-PoP liposomes were effective following systemic administration and local light irradiation in this tumor model, the FA targeting moiety did not appear essential for anti-tumor responses. Full article

(This article belongs to the Special Issue Designing Nanomaterials for Drug Delivery and Cancer-Targeted Therapy)

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18 pages, 6963 KiB

Open AccessEditor’s ChoiceArticle

RNAi-Mediated Knockdown of Cottontail Rabbit Papillomavirus Oncogenes Using Low-Toxicity Lipopolyplexes as a Paradigm to Treat Papillomavirus-Associated Cancers

by Uzma Ali, Michael Bette, Ghazala Ambreen, Shashank R. Pinnapireddy, Imran Tariq, André Marquardt, Boris A. Stuck, Udo Bakowsky and Robert Mandic

Pharmaceutics 2023, 15(10), 2379; https://doi.org/10.3390/pharmaceutics15102379 - 25 Sep 2023

Viewed by 1498

Abstract

The cottontail rabbit papillomavirus (CRPV)-associated VX2 carcinoma of the New Zealand White rabbit serves as a model system for human papillomavirus (HPV)-associated head and neck squamous cell carcinomas (HNSCCs). The aim of this study was to evaluate the tumor-inhibiting effect of RNAi-mediated knockdown [...] Read more.

The cottontail rabbit papillomavirus (CRPV)-associated VX2 carcinoma of the New Zealand White rabbit serves as a model system for human papillomavirus (HPV)-associated head and neck squamous cell carcinomas (HNSCCs). The aim of this study was to evaluate the tumor-inhibiting effect of RNAi-mediated knockdown of the CRPV oncogenes, E6 and E7, using siRNA-loaded lipopolyplexes (LPPs). VX2-carcinoma-derived cells were cultured for up to 150 passages. In addition, CRPV E6 and E7 oncogenes were transiently expressed in COS-7 cells. Efficiency and safety of LPPs were evaluated in both VX2 cells and the COS-7 cell line. Both of these in vitro CRPV systems were validated and characterized by fluorescence microscopy, Western blot, and RT-qPCR. Efficient knockdown of CRPV E6 and E7 was achieved in VX2 cells and COS-7 cells pretransfected with CRPV E6 and E7 expression vectors. Knockdown of CRPV oncogenes in VX2 cells resulted in reduced viability, migration, and proliferation and led to a G0/G1 block in the cell cycle. CRPV E6 and E7 siRNA-loaded LPPs could represent promising therapeutic agents serving as a paradigm for the treatment of papillomavirus-positive cancers and could be of value for the treatment of CRPV-associated diseases in the rabbit such as papillomas and cancers of the skin. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies, 3rd Edition)

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21 pages, 8030 KiB

Open AccessEditor’s ChoiceArticle

A Reversibly Thermoresponsive, Theranostic Nanoemulgel for Tacrolimus Delivery to Activated Macrophages: Formulation and In Vitro Validation

by Riddhi Vichare, Caitlin Crelli, Lu Liu, Amit Chandra Das, Rebecca McCallin, Fatih Zor, Yalcin Kulahci, Vijay S. Gorantla and Jelena M. Janjic

Pharmaceutics 2023, 15(10), 2372; https://doi.org/10.3390/pharmaceutics15102372 - 22 Sep 2023

Cited by 2 | Viewed by 1441

Abstract

Despite long-term immunosuppression, organ transplant recipients face the risk of immune rejection and graft loss. Tacrolimus (TAC, FK506, Prograf^®) is an FDA-approved keystone immunosuppressant for preventing transplant rejection. However, it undergoes extensive first-pass metabolism and has a narrow therapeutic window, which [...] Read more.

Despite long-term immunosuppression, organ transplant recipients face the risk of immune rejection and graft loss. Tacrolimus (TAC, FK506, Prograf^®) is an FDA-approved keystone immunosuppressant for preventing transplant rejection. However, it undergoes extensive first-pass metabolism and has a narrow therapeutic window, which leads to erratic bioavailability and toxicity. Local delivery of TAC directly into the graft, instead of systemic delivery, can improve safety, efficacy, and tolerability. Macrophages have emerged as promising therapeutic targets as their increased levels correlate with an increased risk of organ rejection and a poor prognosis post-transplantation. Here, we present a locally injectable drug delivery platform for macrophages, where TAC is incorporated into a colloidally stable nanoemulsion and then formulated as a reversibly thermoresponsive, pluronic-based nanoemulgel (NEG). This novel formulation is designed to undergo a sol-to-gel transition at physiological temperature to sustain TAC release in situ at the site of local application. We also show that TAC-NEG mitigates the release of proinflammatory cytokines and nitric oxide from lipopolysaccharide (LPS)-activated macrophages. To the best of our knowledge, this is the first TAC-loaded nanoemulgel with demonstrated anti-inflammatory effects on macrophages in vitro. Full article

(This article belongs to the Special Issue Nanoparticles for Targeting and Treating Macrophages)

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36 pages, 11133 KiB

Open AccessEditor’s ChoiceReview

Applications of Degradable Hydrogels in Novel Approaches to Disease Treatment and New Modes of Drug Delivery

by Bo Hu, Jinyuan Gao, Yu Lu and Yuji Wang

Pharmaceutics 2023, 15(10), 2370; https://doi.org/10.3390/pharmaceutics15102370 - 22 Sep 2023

Cited by 3 | Viewed by 1605

Abstract

Hydrogels are particularly suitable materials for loading drug delivery agents; their high water content provides a biocompatible environment for most biomolecules, and their cross-linked nature protects the loaded agents from damage. During delivery, the delivered substance usually needs to be released gradually over [...] Read more.

Hydrogels are particularly suitable materials for loading drug delivery agents; their high water content provides a biocompatible environment for most biomolecules, and their cross-linked nature protects the loaded agents from damage. During delivery, the delivered substance usually needs to be released gradually over time, which can be achieved by degradable cross-linked chains. In recent years, biodegradable hydrogels have become a promising technology in new methods of disease treatment and drug delivery methods due to their many advantageous properties. This review briefly discusses the degradation mechanisms of different types of biodegradable hydrogel systems and introduces the specific applications of degradable hydrogels in several new methods of disease treatment and drug delivery methods. Full article

(This article belongs to the Special Issue Functionalized Nanomaterials for Cancer Therapy)

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17 pages, 5489 KiB

Open AccessEditor’s ChoiceArticle

Penetration of Nanobody-Dextran Polymer Conjugates through Tumor Spheroids

by Peter Bitsch, Eva S. Baum, Irati Beltrán Hernández, Sebastian Bitsch, Jakob Harwood, Sabrina Oliveira and Harald Kolmar

Pharmaceutics 2023, 15(10), 2374; https://doi.org/10.3390/pharmaceutics15102374 - 22 Sep 2023

Viewed by 1732

Abstract

Here we report the generation of nanobody dextran polymer conjugates (dextraknobs) that are loaded with small molecules, i.e., fluorophores or photosensitizers, for potential applications in cancer diagnostics and therapy. To this end, the molecules are conjugated to the dextran polymer which is coupled [...] Read more.

Here we report the generation of nanobody dextran polymer conjugates (dextraknobs) that are loaded with small molecules, i.e., fluorophores or photosensitizers, for potential applications in cancer diagnostics and therapy. To this end, the molecules are conjugated to the dextran polymer which is coupled to the C-terminus of an EGFR-specific nanobody using chemoenzymatic approaches. A monovalent EGFR-targeted nanobody and biparatopic version modified with different dextran average molecular weights (1000, 5000, and 10,000) were probed for their ability to penetrate tumor spheroids. For monovalent Cy5-labeled dextraknobs, the utilization of smaller sized dextran (MW 5000 vs. 10,000) was found to be beneficial for more homogeneous penetration into A431 tumor spheroids over time. For the biparatopic dual nanobody comprising MW 1000, 5000, and 10,000 dextran labeled with photosensitizer IRDye700DX, penetration behavior was comparable to that of a direct nanobody-photosensitizer conjugate lacking a dextran scaffold. Additionally, dextraknobs labeled with IRDye700DX incubated with cells in 2D and 3D showed potent cell killing upon illumination, thus inducing photodynamic therapy (PDT). In line with previous results, monovalent nanobody conjugates displayed deeper and more homogenous penetration through spheroids than the bivalent conjugates. Importantly, the smaller size dextrans did not affect the distribution of the conjugates, thus encouraging further development of dextraknobs. Full article

(This article belongs to the Special Issue Photodynamic Therapy in Cancer: Principles, State of the Art, and Future Directions)

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17 pages, 3467 KiB

Open AccessEditor’s ChoiceArticle

Evaluation of a Novel Dry Powder Surfactant Aerosol Delivery System for Use in Premature Infants Supported with Bubble CPAP

by Robert M. DiBlasi, Coral N. Crandall, Rebecca J. Engberg, Kunal Bijlani, Dolena Ledee, Masaki Kajimoto and Frans J. Walther

Pharmaceutics 2023, 15(10), 2368; https://doi.org/10.3390/pharmaceutics15102368 - 22 Sep 2023

Cited by 1 | Viewed by 1502

Abstract

Aerosolized lung surfactant therapy during nasal continuous positive airway pressure (CPAP) support avoids intubation but is highly complex, with reported poor nebulizer efficiency and low pulmonary deposition. The study objective was to evaluate particle size, operational compatibility, and drug delivery efficiency with various [...] Read more.

Aerosolized lung surfactant therapy during nasal continuous positive airway pressure (CPAP) support avoids intubation but is highly complex, with reported poor nebulizer efficiency and low pulmonary deposition. The study objective was to evaluate particle size, operational compatibility, and drug delivery efficiency with various nasal CPAP interfaces and gas humidity levels of a synthetic dry powder (DP) surfactant aerosol delivered by a low-flow aerosol chamber (LFAC) inhaler combined with bubble nasal CPAP (bCPAP). A particle impactor characterized DP surfactant aerosol particle size. Lung pressures and volumes were measured in a preterm infant nasal airway and lung model using LFAC flow injection into the bCPAP system with different nasal prongs. The LFAC was combined with bCPAP and a non-heated passover humidifier. DP surfactant mass deposition within the nasal airway and lung was quantified for different interfaces. Finally, surfactant aerosol therapy was investigated using select interfaces and bCPAP gas humidification by active heating. Surfactant aerosol particle size was 3.68 µm. Lung pressures and volumes were within an acceptable range for lung protection with LFAC actuation and bCPAP. Aerosol delivery of DP surfactant resulted in variable nasal airway (0–20%) and lung (0–40%) deposition. DP lung surfactant aerosols agglomerated in the prongs and nasal airways with significant reductions in lung delivery during active humidification of bCPAP gas. Our findings show high-efficiency delivery of small, synthetic DP surfactant particles without increasing the potential risk for lung injury during concurrent aerosol delivery and bCPAP with passive humidification. Specialized prongs adapted to minimize extrapulmonary aerosol losses and nasal deposition showed the greatest lung deposition. The use of heated, humidified bCPAP gases compromised drug delivery and safety. Safety and efficacy of DP aerosol delivery in preterm infants supported with bCPAP requires more research. Full article

(This article belongs to the Section Drug Delivery and Controlled Release)

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21 pages, 3302 KiB

Open AccessEditor’s ChoiceArticle

New Hybrid Compounds Incorporating Natural Products as Multifunctional Agents against Alzheimer’s Disease

by Lidia Ciccone, Caterina Camodeca, Nicolò Tonali, Lucia Barlettani, Armando Rossello, Carole Fruchart Gaillard, Julia Kaffy, Giovanni Petrarolo, Concettina La Motta, Susanna Nencetti and Elisabetta Orlandini

Pharmaceutics 2023, 15(10), 2369; https://doi.org/10.3390/pharmaceutics15102369 - 22 Sep 2023

Viewed by 1021

Abstract

A series of new hybrid derivatives 1a–c, 2a–c, 3a–c, 4a–c, 5a–c, inspired by nature, were synthesized and studied as multifunctional agents for the treatment of Alzheimer’s disease (AD). [...] Read more.

A series of new hybrid derivatives 1a–c, 2a–c, 3a–c, 4a–c, 5a–c, inspired by nature, were synthesized and studied as multifunctional agents for the treatment of Alzheimer’s disease (AD). These compounds were designed to merge together the trifluoromethyl benzyloxyaminic bioactive moiety, previously identified, with different acids available in nature. The ability of the synthesized compounds to chelate biometals, such as Cu²⁺, Zn²⁺ and Fe²⁺, was studied by UV–Vis spectrometer, and through a preliminary screening their antioxidant activity was evaluated by DPPH. Then, selected compounds were tested by in vitro ABTS free radical method and ex vivo rat brain TBARS assay. Compounds 2a–c, combining the strongest antioxidant and biometal chelators activities, were studied for their ability to contrast Aβ_1-40 fibrillization process. Finally, starting from the promising profile obtained for compound 2a, we evaluated if it could be able to induce a positive cross-interaction between transthyretin (TTR) and Aβ in presence and in absence of Cu²⁺. Full article

(This article belongs to the Special Issue New Insights on Drug Design, Delivery and Targeting in Neurodegeneration)

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23 pages, 5779 KiB

Open AccessEditor’s ChoiceArticle

Development of 3D-Printed Bicompartmental Devices by Dual-Nozzle Fused Deposition Modeling (FDM) for Colon-Specific Drug Delivery

by Fatemeh Shojaie, Carmen Ferrero and Isidoro Caraballo

Pharmaceutics 2023, 15(9), 2362; https://doi.org/10.3390/pharmaceutics15092362 - 21 Sep 2023

Cited by 2 | Viewed by 1468

Abstract

Dual-nozzle fused deposition modeling (FDM) is a 3D printing technique that allows for the simultaneous printing of two polymeric filaments and the design of complex geometries. Hence, hybrid formulations and structurally different sections can be combined into the same dosage form to achieve [...] Read more.

Dual-nozzle fused deposition modeling (FDM) is a 3D printing technique that allows for the simultaneous printing of two polymeric filaments and the design of complex geometries. Hence, hybrid formulations and structurally different sections can be combined into the same dosage form to achieve customized drug release kinetics. The objective of this study was to develop a novel bicompartmental device by dual-nozzle FDM for colon-specific drug delivery. Hydroxypropylmethylcellulose acetate succinate (HPMCAS) and polyvinyl alcohol (PVA) were selected as matrix-forming polymers of the outer pH-dependent and the inner water-soluble compartments, respectively. 5-Aminosalicylic acid (5-ASA) was selected as the model drug. Drug-free HPMCAS and drug-loaded PVA filaments suitable for FDM were extruded, and their properties were assessed by thermal, X-ray diffraction, microscopy, and texture analysis techniques. 5-ASA (20% w/w) remained mostly crystalline in the PVA matrix. Filaments were successfully printed into bicompartmental devices combining an outer cylindrical compartment and an inner spiral-shaped compartment that communicates with the external media through an opening. Scanning electron microscopy and X-ray tomography analysis were performed to guarantee the quality of the 3D-printed devices. In vitro drug release tests demonstrated a pH-responsive biphasic release pattern: a slow and sustained release period (pH values of 1.2 and 6.8) controlled by drug diffusion followed by a faster drug release phase (pH 7.4) governed by polymer relaxation/erosion. Overall, this research demonstrates the feasibility of the dual-nozzle FDM technique to obtain an innovative 3D-printed bicompartmental device for targeting 5-ASA to the colon. Full article

(This article belongs to the Special Issue 3D Printing Technology for Pharmaceutical and Biomedical Application)

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38 pages, 2567 KiB

Open AccessEditor’s ChoiceReview

Advances in Pancreatic Cancer Treatment by Nano-Based Drug Delivery Systems

by Cláudia Viegas, Ana B. Patrício, João Prata, Leonor Fonseca, Ana S. Macedo, Sofia O. D. Duarte and Pedro Fonte

Pharmaceutics 2023, 15(9), 2363; https://doi.org/10.3390/pharmaceutics15092363 - 21 Sep 2023

Cited by 6 | Viewed by 2614

Abstract

Pancreatic cancer represents one of the most lethal cancer types worldwide, with a 5-year survival rate of less than 5%. Due to the inability to diagnose it promptly and the lack of efficacy of existing treatments, research and development of innovative therapies and [...] Read more.

Pancreatic cancer represents one of the most lethal cancer types worldwide, with a 5-year survival rate of less than 5%. Due to the inability to diagnose it promptly and the lack of efficacy of existing treatments, research and development of innovative therapies and new diagnostics are crucial to increase the survival rate and decrease mortality. Nanomedicine has been gaining importance as an innovative approach for drug delivery and diagnosis, opening new horizons through the implementation of smart nanocarrier systems, which can deliver drugs to the specific tissue or organ at an optimal concentration, enhancing treatment efficacy and reducing systemic toxicity. Varied materials such as lipids, polymers, and inorganic materials have been used to obtain nanoparticles and develop innovative drug delivery systems for pancreatic cancer treatment. In this review, it is discussed the main scientific advances in pancreatic cancer treatment by nano-based drug delivery systems. The advantages and disadvantages of such delivery systems in pancreatic cancer treatment are also addressed. More importantly, the different types of nanocarriers and therapeutic strategies developed so far are scrutinized. Full article

(This article belongs to the Topic Applications of Polymers and Polymer Nanomaterials in Drug Delivery and Nanomedicine)

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17 pages, 1406 KiB

Open AccessEditor’s ChoiceReview

Personalized and Precision Medicine in Asthma and Eosinophilic Esophagitis: The Role of T2 Target Therapy

by Diego Bagnasco, Edoardo Vincenzo Savarino, Mona-Rita Yacoub, Fulvio Braido, Maria Giulia Candeliere, Edoardo Giannini, Giovanni Passalacqua and Elisa Marabotto

Pharmaceutics 2023, 15(9), 2359; https://doi.org/10.3390/pharmaceutics15092359 - 21 Sep 2023

Viewed by 1357

Abstract

The role of type 2 inflammation has been progressively associated with many diseases, including severe asthma, atopic dermatitis, nasal polyposis, eosinophilic granulomatosis with polyangiitis, and, recently, eosinophilic esophagitis. Despite this, the association between asthma and esophagitis is still poorly known, and this is [...] Read more.

The role of type 2 inflammation has been progressively associated with many diseases, including severe asthma, atopic dermatitis, nasal polyposis, eosinophilic granulomatosis with polyangiitis, and, recently, eosinophilic esophagitis. Despite this, the association between asthma and esophagitis is still poorly known, and this is probably because of the low prevalence of each disease and the even lower association between them. Nonetheless, observations in clinical trials and, subsequently, in real life, have allowed researchers to observe how drugs acting on type 2 inflammation, initially developed and marketed for severe asthma, could be effective also in treating eosinophilic esophagitis. For this reason, clinical trials specifically designed for the use of drugs targeted to type 2 inflammation were also developed for eosinophilic esophagitis. The results of clinical trials are presently promising and envisage the use of biologicals that are also likely to be employed in the field of gastroenterology in the near future. This review focuses on the use of biologicals for type 2 inflammation in cases of combined severe asthma and eosinophilic esophagitis. Full article

(This article belongs to the Section Biologics and Biosimilars)

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20 pages, 2936 KiB

Open AccessEditor’s ChoiceArticle

Hydroxypropyl Methylcellulose Bioadhesive Hydrogels for Topical Application and Sustained Drug Release: The Effect of Polyvinylpyrrolidone on the Physicomechanical Properties of Hydrogel

by Patrick Pan, Darren Svirskis, Geoffrey I. N. Waterhouse and Zimei Wu

Pharmaceutics 2023, 15(9), 2360; https://doi.org/10.3390/pharmaceutics15092360 - 21 Sep 2023

Cited by 5 | Viewed by 2708

Abstract

Hydrogels are homogeneous three-dimensional polymeric networks capable of holding large amounts of water and are widely used in topical formulations. Herein, the physicomechanical, rheological, bioadhesive, and drug-release properties of hydrogels containing hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP) were examined, and the intermolecular interactions [...] Read more.

Hydrogels are homogeneous three-dimensional polymeric networks capable of holding large amounts of water and are widely used in topical formulations. Herein, the physicomechanical, rheological, bioadhesive, and drug-release properties of hydrogels containing hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP) were examined, and the intermolecular interactions between the polymers were explored. A three-level factorial design was used to form HPMC–PVP binary hydrogels. The physicomechanical properties of the binary hydrogels alongside the homopolymeric HPMC hydrogels were characterized using a texture analyzer. Rheological properties of the gels were studied using a cone and plate rheometer. The bioadhesiveness of selected binary hydrogels was tested on porcine skin. Hydrophilic benzophenone-4 was loaded into both homopolymeric and binary gels, and drug-release profiles were investigated over 24 h at 33 °C. Fourier transform infrared spectroscopy (FTIR) was used to understand the inter-molecular drug–gel interactions. Factorial design analysis supported the dominant role of the HPMC in determining the gel properties, rather than the PVP, with the effect of both polymer concentrations being non-linear. The addition of PVP to the HPMC gels improved adhesiveness without significantly affecting other properties such as hardness, shear-thinning feature, and viscosity, thereby improving bioadhesiveness for sustained skin retention without negatively impacting cosmetic acceptability or ease of use. The release of benzophenone-4 in the HPMC hydrogels followed zero-order kinetics, with benzophenone-4 release being significantly retarded by the presence of PVP, likely due to intermolecular interactions between the drug and the PVP polymer, as confirmed by the FTIR. The HPMC–PVP binary hydrogels demonstrate strong bioadhesiveness resulting from the addition of PVP with desirable shear-thinning properties that allow the formulation to have extended skin-retention times. The developed HPMC–PVP binary hydrogel is a promising sustained-release platform for topical drug delivery. Full article

(This article belongs to the Special Issue Recent Advances in Long-Acting Drug Delivery and Formulations)

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14 pages, 2255 KiB

Open AccessEditor’s ChoiceArticle

Camellia sinensis (L.) Kuntze Extract Attenuates Ovalbumin-Induced Allergic Asthma by Regulating Airway Inflammation and Mucus Hypersecretion

by Sohi Kang, Hyun-Yong Kim, A Yeong Lee, Hyo Seon Kim, Jun Hong Park, Byeong Cheol Moon, Hyeon Hwa Nam, Sung-Wook Chae, Bokyung Jung, Changjong Moon, In Sik Shin, Joong Sun Kim and Yun-Soo Seo

Pharmaceutics 2023, 15(9), 2355; https://doi.org/10.3390/pharmaceutics15092355 - 20 Sep 2023

Cited by 3 | Viewed by 1262

Abstract

Asthma is a pulmonary disease induced by the inhalation of aeroallergens and subsequent inappropriate immune responses. Camellia sinensis (L.) Kuntze has been evaluated as an effective antioxidant supplement produced from bioactive compounds, including flavonoids. In this study, we aimed to determine the effects [...] Read more.

Asthma is a pulmonary disease induced by the inhalation of aeroallergens and subsequent inappropriate immune responses. Camellia sinensis (L.) Kuntze has been evaluated as an effective antioxidant supplement produced from bioactive compounds, including flavonoids. In this study, we aimed to determine the effects of Camellia sinensis (L.) Kuntze extract (CE) on ovalbumin-induced allergic asthma. The components of CE were analyzed using high-performance liquid chromatography (HPLC) chromatogram patterns, and asthmatic animal models were induced via ovalbumin treatment. The antioxidant and anti-inflammatory effects of CE were evaluated using 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH), 2,2′-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS), and nitric oxide (NO) assays. Seven compounds were detected in the CE chromatogram. In the ovalbumin-induced mouse model, CE treatment significantly decreased the inflammation index in the lung tissue. CE also significantly decreased eosinophilia and the production of inflammatory cytokines and OVA-specific IgE in animals with asthma. Collectively, our results indicate that CE has anti-inflammatory and antioxidant activities, and that CE treatment suppresses asthmatic progression, including mucin accumulation, inflammation, and OVA-specific IgE production. Full article

(This article belongs to the Special Issue New Approach to Anti-inflammation, Antibacterial and Anti-cancer Therapy: Natural Extracts)

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21 pages, 5928 KiB

Open AccessEditor’s ChoiceArticle

Inhalable Combination Powder Formulations for Treating Latent and Multidrug-Resistant Tuberculosis: Formulation and In Vitro Characterization

by Basanth Babu Eedara, Claire Fan, Shubhra Sinha, Prakash Khadka and Shyamal C. Das

Pharmaceutics 2023, 15(9), 2354; https://doi.org/10.3390/pharmaceutics15092354 - 20 Sep 2023

Cited by 1 | Viewed by 1496

Abstract

Tuberculosis (TB) is an infectious disease resulting in millions of deaths annually worldwide. TB treatment is challenging due to a huge number of global latent infections and due to multidrug-resistant forms of TB. Inhaled administration of anti-TB drugs using dry powder inhalers has [...] Read more.

Tuberculosis (TB) is an infectious disease resulting in millions of deaths annually worldwide. TB treatment is challenging due to a huge number of global latent infections and due to multidrug-resistant forms of TB. Inhaled administration of anti-TB drugs using dry powder inhalers has various advantages over oral administration due to its direct drug delivery and minimization of systemic side effects. Pretomanid (PA-824, PA) is a relatively new drug with potent activity against both active and latent forms of Mycobacterium tuberculosis (Mtb). It is also known for its synergistic effects in combination with pyrazinamide (PYR) and moxifloxacin (MOX). Fixed-dose combination powder formulations of either PYR and PA or PYR and MOX were prepared for inhaled delivery to the deep lung regions where the Mtb habitats were located. Powder formulations were prepared by spray drying using L-leucine as the aerosolization enhancer and were characterized by their particle size, morphology and solid-state properties. In vitro aerosolization behaviour was studied using a Next Generation Impactor, and stability was assessed after storage at room temperature and 30% relative humidity for three months. Spray drying with L-leucine resulted in spherical dimpled particles, 1.9 and 2.4 µm in size for PYR-PA and PYR-MOX combinations, respectively. The powder formulations had an emitted dose of >83% and a fine particle fraction of >65%. PA and MOX showed better stability in the combination powders compared to PYR. Combination powder formulations with high aerosolization efficiency for direct delivery to the lungs were developed in this study for use in the treatment of latent and multidrug-resistant TB infections. Full article

(This article belongs to the Special Issue Recent Advances in Amorphous Drug)

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12 pages, 2232 KiB

Open AccessEditor’s ChoiceArticle

A New Paclitaxel Formulation Based on Secretome Isolated from Mesenchymal Stem Cells Shows a Significant Cytotoxic Effect on Osteosarcoma Cell Lines

by Alessia Giovanna Santa Banche Niclot, Elena Marini, Ivana Ferrero, Francesco Barbero, Elena Rosso, Ivana Fenoglio, Alessandro Barge, Augusto Pessina, Valentina Coccè, Francesca Paino, Katia Mareschi and Franca Fagioli

Pharmaceutics 2023, 15(9), 2340; https://doi.org/10.3390/pharmaceutics15092340 - 19 Sep 2023

Cited by 1 | Viewed by 1197

Abstract

Background: Osteosarcoma (OS) represents a rare cancer with an unfavorable prognosis that needs innovative treatment. The aim was to isolate a secretome from mesenchymal stem cells (MSCs) that are treated with paclitaxel (PTX)-containing microvesicles as a drug delivery system and analyze its cytotoxic [...] Read more.

Background: Osteosarcoma (OS) represents a rare cancer with an unfavorable prognosis that needs innovative treatment. The aim was to isolate a secretome from mesenchymal stem cells (MSCs) that are treated with paclitaxel (PTX)-containing microvesicles as a drug delivery system and analyze its cytotoxic effects on OS cell lines (SJSA, MG63, and HOS). Methods: Three batches of secretome (SECR-1, SECR-2, and SECR-3) were produced from three bone marrow (BM) MSCs samples treated for 24 h with 15 µg/mL of PTX or with a standard medium. The viability of the OS cell lines after 5 days of exposure to SECR-1-2-3 (pure and diluted to 1:2 and 1:4) was analyzed with an MTT assay. The same SECR batches were analyzed with high-performance liquid chromatography (HPLC) and with a nanoparticle tracking assay (NTA). Results: A statistically significant decrease in the viability of all OS cell lines was observed after treatment with SECR-PTX 1-2-3 in a dose–response manner. The NTA analyses showed the presence of nanoparticles (NPs) with a mean size comparable to that of extracellular vesicles (EVs). The HPLC analyses detected the presence of PTX in minimal doses in all SECR batches. Conclusions: This proof-of-concept study showed that the conditioned medium isolated from MSCs loaded with PTX had a strong cytotoxic effect on OS cell lines, due to the presence of EV and PTX. Full article

(This article belongs to the Special Issue Mesenchymal Stem/Stromal Cell-Based-Delivery for Clinical Applications)

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33 pages, 8301 KiB

Open AccessEditor’s ChoiceReview

Photothermal Effect of Gold Nanoparticles as a Nanomedicine for Diagnosis and Therapeutics

by Panangattukara Prabhakaran Praveen Kumar and Dong-Kwon Lim

Pharmaceutics 2023, 15(9), 2349; https://doi.org/10.3390/pharmaceutics15092349 - 19 Sep 2023

Cited by 15 | Viewed by 3047

Abstract

Gold nanoparticles (AuNPs) have received great attention for various medical applications due to their unique physicochemical properties. AuNPs with tunable optical properties in the visible and near-infrared regions have been utilized in a variety of applications such as in vitro diagnostics, in vivo [...] Read more.

Gold nanoparticles (AuNPs) have received great attention for various medical applications due to their unique physicochemical properties. AuNPs with tunable optical properties in the visible and near-infrared regions have been utilized in a variety of applications such as in vitro diagnostics, in vivo imaging, and therapeutics. Among the applications, this review will pay more attention to recent developments in diagnostic and therapeutic applications based on the photothermal (PT) effect of AuNPs. In particular, the PT effect of AuNPs has played an important role in medical applications utilizing light, such as photoacoustic imaging, photon polymerase chain reaction (PCR), and hyperthermia therapy. First, we discuss the fundamentals of the optical properties in detail to understand the background of the PT effect of AuNPs. For diagnostic applications, the ability of AuNPs to efficiently convert absorbed light energy into heat to generate enhanced acoustic waves can lead to significant enhancements in photoacoustic signal intensity. Integration of the PT effect of AuNPs with PCR may open new opportunities for technological innovation called photonic PCR, where light is used to enable fast and accurate temperature cycling for DNA amplification. Additionally, beyond the existing thermotherapy of AuNPs, the PT effect of AuNPs can be further applied to cancer immunotherapy. Controlled PT damage to cancer cells triggers an immune response, which is useful for obtaining better outcomes in combination with immune checkpoint inhibitors or vaccines. Therefore, this review examines applications to nanomedicine based on the PT effect among the unique optical properties of AuNPs, understands the basic principles, the advantages and disadvantages of each technology, and understands the importance of a multidisciplinary approach. Based on this, it is expected that it will help understand the current status and development direction of new nanoparticle-based disease diagnosis methods and treatment methods, and we hope that it will inspire the development of new innovative technologies. Full article

(This article belongs to the Special Issue Advances in Cancer Nanotechnology for Photodynamic and Photothermal Therapy)

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53 pages, 8211 KiB

Open AccessEditor’s ChoiceReview

Cyclodextrin Inclusion Complexes for Improved Drug Bioavailability and Activity: Synthetic and Analytical Aspects

by Álvaro Sarabia-Vallejo, María del Mar Caja, Ana I. Olives, M. Antonia Martín and J. Carlos Menéndez

Pharmaceutics 2023, 15(9), 2345; https://doi.org/10.3390/pharmaceutics15092345 - 19 Sep 2023

Cited by 21 | Viewed by 3801

Abstract

Many active pharmaceutical ingredients show low oral bioavailability due to factors such as poor solubility and physical and chemical instability. The formation of inclusion complexes with cyclodextrins, as well as cyclodextrin-based polymers, nanosponges, and nanofibers, is a valuable tool to improve the oral [...] Read more.

Many active pharmaceutical ingredients show low oral bioavailability due to factors such as poor solubility and physical and chemical instability. The formation of inclusion complexes with cyclodextrins, as well as cyclodextrin-based polymers, nanosponges, and nanofibers, is a valuable tool to improve the oral bioavailability of many drugs. The microencapsulation process modifies key properties of the included drugs including volatility, dissolution rate, bioavailability, and bioactivity. In this context, we present relevant examples of the stabilization of labile drugs through the encapsulation in cyclodextrins. The formation of inclusion complexes with drugs belonging to class IV in the biopharmaceutical classification system as an effective solution to increase their bioavailability is also discussed. The stabilization and improvement in nutraceuticals used as food supplements, which often have low intestinal absorption due to their poor solubility, is also considered. Cyclodextrin-based nanofibers, which are polymer-free and can be generated using environmentally friendly technologies, lead to dramatic bioavailability enhancements. The synthesis of chemically modified cyclodextrins, polymers, and nanosponges based on cyclodextrins is discussed. Analytical techniques that allow the characterization and verification of the formation of true inclusion complexes are also considered, taking into account the differences in the procedures for the formation of inclusion complexes in solution and in the solid state. Full article

(This article belongs to the Special Issue Development of Chitosan/Cyclodextrins in Drug Delivery Field)

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14 pages, 3158 KiB

Open AccessEditor’s ChoiceArticle

Caco-2 Cell Sheet Partially Laminated with HT29-MTX Cells as a Novel In Vitro Model of Gut Epithelium Drug Permeability

by Yi Cheng, Chie Watanabe, Yusuke Ando, Satoshi Kitaoka, Yuya Egawa, Tomoya Takashima, Akihiro Matsumoto and Masahiro Murakami

Pharmaceutics 2023, 15(9), 2338; https://doi.org/10.3390/pharmaceutics15092338 - 18 Sep 2023

Cited by 2 | Viewed by 1849

Abstract

The intestinal epithelial Caco-2 cell monolayer is a well-established in vitro model useful for predicting intestinal drug absorption in humans. Coculture models of Caco-2 and goblet-cell-like HT29-MTX cells have been developed to overcome the lack of a mucus layer; however, those models are [...] Read more.

The intestinal epithelial Caco-2 cell monolayer is a well-established in vitro model useful for predicting intestinal drug absorption in humans. Coculture models of Caco-2 and goblet-cell-like HT29-MTX cells have been developed to overcome the lack of a mucus layer; however, those models are much leakier compared to the intestinal epithelium. Here, we developed a partially laminated culture model where HT29-MTX cells were superimposed onto a Caco-2 monolayer to overcome this issue. A morphological study showed that the piled HT29-MTX cells were voluntarily incorporated into the Caco-2 monolayer, and mucus production was confirmed via periodic acid-Schiff and mucin protein 2 staining. Permeability was evaluated in terms of transepithelial electrical resistance (TEER) and the apparent permeability of paracellular markers with different molecular sizes. The partially laminated model maintained the high barrier function of the Caco-2 monolayer, whose permeability appeared adjustable according to the HT29-MTX/Caco-2 cell ratio. In contrast, the coculture models showed abnormally high permeability of those markers, correlated with low TEER. Thus, the partially laminated model enabled in vitro recapitulation of effective mucosal barrier function. Consequently, this novel model may be useful as an in vitro high-throughput evaluation system for enteral mucosal permeability and mucus-penetrating efficiency of drugs and nanocarriers. Full article

(This article belongs to the Special Issue The Latest Technology for the Prediction and Improvement of Drug Absorption)

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17 pages, 3931 KiB

Open AccessEditor’s ChoiceArticle

Conjugation with Tris Decreases the Risk of Ketoprofen-Induced Mucosal Damage and Reduces Inflammation-Associated Methane Production in a Rat Model of Colitis

by Melinda Ugocsai, Anett Bársony, Réka Anna Varga, Ámos Gajda, Noémi Vida, Norbert Lajkó, Benedek Rónaszéki, Gábor Tóth, Mihály Boros, Dániel Érces and Gabriella Varga

Pharmaceutics 2023, 15(9), 2329; https://doi.org/10.3390/pharmaceutics15092329 - 16 Sep 2023

Viewed by 942

Abstract

We have designed a new compound from the non-steroidal anti-inflammatory drug (NSAID) ketoprofen (Ket) and 2-amino-2-(hydroxymethyl)-1,3-propanediol (Tris) precursors, with the aim to reduce the gastrointestinal (GI) side effects of NSAID therapies. We investigated mucosal reactions in a standard rat model of colitis together [...] Read more.

We have designed a new compound from the non-steroidal anti-inflammatory drug (NSAID) ketoprofen (Ket) and 2-amino-2-(hydroxymethyl)-1,3-propanediol (Tris) precursors, with the aim to reduce the gastrointestinal (GI) side effects of NSAID therapies. We investigated mucosal reactions in a standard rat model of colitis together with methane generation as a possible indicator of pro-inflammatory activation under this condition (approval number: V./148/2013). Whole-body methane production (photoacoustic spectroscopy) and serosal microcirculation (intravital videomicroscopy) were measured, and mucosal damage was assessed (conventional histology; in vivo laser-scanning endomicroscopy). Inflammatory markers were measured from tissue and blood samples. Colitis induced an inflammatory response, morphological colonic damage and increased methane output. Ket treatment lowered inflammatory activation and colonic mucosal injury, but macroscopic gastric bleeding and increased methane output were present. Ket-Tris reduced inflammatory activation, methane emission and colonic mucosal damage, without inducing gastric injury. Conjugation with Tris reduces the GI side effects of Ket and still decreases the inflammatory response in experimental colitis. Methane output correlates with the mucosal inflammatory response and non-invasively demonstrates the effects of anti-inflammatory treatments. Full article

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28 pages, 3985 KiB

Open AccessEditor’s ChoiceArticle

Intracellular Fate of the Photosensitizer Chlorin e4 with Different Carriers and Induced Metabolic Changes Studied by ¹H NMR Spectroscopy

by Martina Vermathen, Tobias Kämpfer, Jean-Marc Nuoffer and Peter Vermathen

Pharmaceutics 2023, 15(9), 2324; https://doi.org/10.3390/pharmaceutics15092324 - 15 Sep 2023

Cited by 1 | Viewed by 1013

Abstract

Porphyrinic photosensitizers (PSs) and their nano-sized polymer-based carrier systems are required to exhibit low dark toxicity, avoid side effects, and ensure high in vivo tolerability. Yet, little is known about the intracellular fate of PSs during the dark incubation period and how it [...] Read more.

Porphyrinic photosensitizers (PSs) and their nano-sized polymer-based carrier systems are required to exhibit low dark toxicity, avoid side effects, and ensure high in vivo tolerability. Yet, little is known about the intracellular fate of PSs during the dark incubation period and how it is affected by nanoparticles. In a systematic study, high-resolution magic angle spinning NMR spectroscopy combined with statistical analyses was used to study the metabolic profile of cultured HeLa cells treated with different concentrations of PS chlorin e4 (Ce4) alone or encapsulated in carrier systems. For the latter, either polyvinylpyrrolidone (PVP) or the micelle-forming polyethylene glycol (PEG)-polypropylene glycol triblock copolymer Kolliphor P188 (KP) were used. Diffusion-edited spectra indicated Ce4 membrane localization evidenced by Ce4 concentration-dependent chemical shift perturbation of the cellular phospholipid choline resonance. The effect was also visible in the presence of KP and PVP but less pronounced. The appearance of the PEG resonance in the cell spectra pointed towards cell internalization of KP, whereas no conclusion could be drawn for PVP that remained NMR-invisible. Multivariate statistical analyses of the cell spectra (PCA, PLS-DA, and oPLS) revealed a concentration-dependent metabolic response upon exposure to Ce4 that was attenuated by KP and even more by PVP. Significant Ce4-concentration-dependent alterations were mainly found for metabolites involved in the tricarboxylic acid cycle and the phosphatidylcholine metabolism. The data underline the important protective role of the polymeric carriers following cell internalization. Moreover, to our knowledge, for the first time, the current study allowed us to trace intracellular PS localization on an atomic level by NMR methods. Full article

(This article belongs to the Section Gene and Cell Therapy)

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